ORCID Profile
0000-0003-1301-405X
Current Organisations
Australian National University
,
University of Sydney
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Applied Statistics | Statistics | Bioinformatics | Gene Expression (incl. Microarray and other genome-wide approaches) | Biochemistry and Cell Biology | Gene Expression | Cell Development (Incl. Cell Division And Apoptosis) | Animal Physiology—Systems | Pattern Recognition and Data Mining |
ANZSRC Socio-Economic Objective (SEO)
Cancer and Related Disorders | Expanding Knowledge in the Mathematical Sciences | Nervous system and disorders | Blood disorders | Skin and related disorders | Expanding Knowledge in the Medical and Health Sciences
Related Links
Publications
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541629
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541626
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Identifying the ‘Active Ingredients' of an Effective Psychological Intervention to Reduce Fear of Cancer Recurrence: A Process Evaluation
Publisher: Frontiers Media SA
Date: 07-06-2021
DOI: 10.3389/FPSYG.2021.661190
Abstract: Purpose: Psychological interventions targeting fear of cancer recurrence (FCR) are effective in reducing fear and distress. Process evaluations are an important, yet scarce adjunct to published intervention trials, despite their utility in guiding the interpretation of study outcomes and optimizing intervention design for broader implementation. Accordingly, this paper reports the findings of a process evaluation conducted alongside a randomized controlled trial of a psychological intervention for melanoma patients. Methods: Men and women with a history of Stage 0–II melanoma at high-risk of developing new primary disease were recruited via High Risk Melanoma Clinics across Sydney, Australia and randomly allocated to receive the psychological intervention ( n = 80) or usual care ( n = 84). Intervention participants received a tailored psycho-educational resource and three in idual psychotherapeutic sessions delivered via telehealth. Qualitative and quantitative data on intervention context, processes, and delivery (reach, dose, and fidelity), and mechanisms of impact (participant responses, moderators of outcome) were collected from a range of sources, including participant surveys, psychotherapeutic session audio-recordings, and clinical records. Results: Almost all participants reported using the psycho-educational resource (97%), received all intended psychotherapy sessions (96%), and reported high satisfaction with both intervention components. Over 80% of participants would recommend the intervention to others, and a small proportion (4%) found discussion of melanoma-related experiences confronting. Perceived benefits included enhanced doctor-patient communication, talking more openly with family members about melanoma, and improved coping. Of potential moderators, only higher FCR severity at baseline (pre-intervention) was associated with greater reductions in FCR severity (primary outcome) at 6-month follow-up (primary endpoint). Conclusions: Findings support the acceptability and feasibility of a psychological intervention to reduce FCR amongst in iduals at high risk of developing another melanoma. Implementation into routine melanoma care is an imperative next step, with FCR screening recommended to identify those most likely to derive the greatest psychological benefit.
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541620
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541623
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Identification of a melanoma susceptibility locus and somatic mutation inTET2
Publisher: Oxford University Press (OUP)
Date: 30-06-2014
Better the Devil You Know? High‐Risk Individuals’ Anticipated Psychological Responses to Genetic Testing for Melanoma Susceptibility
Publisher: Wiley
Date: 14-11-2006
DOI: 10.1007/S10897-006-9038-3
Abstract: The psychological consequences of genetic testing for mutations among in iduals at increased risk of developing melanoma remain unexamined. The present study aimed to explore anticipated emotional, behavioral, cognitive, and familial responses to hypothetical genetic testing for melanoma susceptibility. Forty semi-structured interviews were undertaken with affected (n=20) and unaffected (n=20) in iduals at either high or average risk of developing melanoma due to family history. In-depth thematic analysis revealed that, in response to being identified as a mutation carrier, most participants with a family history anticipated calmly accepting their increased risk either increasing precaution adoption or maintaining already vigilant behavioral practices perceiving such information as important and valuable and communicating genetic test results to family members, despite the acknowledgement of potential difficulties. In response to being identified as a non-carrier, the majority of participants expected to feel relieved to maintain current precautionary health practices to still perceive themselves at some risk of developing melanoma and to be wary of the potential negative behavioral consequences of disclosing such information to family members. Women appeared more likely than men to acknowledge the potential for depression and worry following genetic testing. In contrast, more males than females expected to carry a gene mutation, and viewed their current preventive practices as optimum. Genetic testing for melanoma risk is likely to elicit a complex array of emotional, behavioral, cognitive, and familial responses for both testees and their family members, and these responses are likely to bear subtle differences for males and females.
Tape Stripped Stratum Corneum Samples Prove to be Suitable for Comprehensive Proteomic Investigation of Actinic Keratosis
Publisher: Wiley
Date: 08-10-2018
Abstract: Actinic keratoses (AK) are premalignant tumors that can be clinically difficult to differentiate from skin cancer. An easy, quick, and reliable noninvasive alternative to biopsy is needed to definitively confirm the clinical diagnoses. This study evaluates Tape Stripping (TS) of stratum corneum (SC) for noninvasive biomarker analysis of AK. Lesional and nonlesional human SC s les are obtained by application of stripping tapes on the skin of five AK patients. Following s le preparation, protein digests are analyzed by LC-MS/MS. Bioinformatics analyses are performed using Funrich, Ingenuity Pathway Analysis (IPA), and Oncomine bioinformatics and analytical tools. Of the total 613 unique proteins identified, 477 overlap with proteins identified in the proteomic analysis of formalin-fixed and paraffin-embedded (FFPE) AK s les. Additionally, 32 proteins are significantly increased and four proteins decreased in AK s les compared to the normal skin (p < 0.05). In line with proteomic analysis of FFPE s les, IPA and Funrich analysis show that differentially abundant proteins in the TS AK s les are implicated in PI3K/AKT and EGF signaling pathways. These findings are confirmed at the transcript level. Tape stripped AK s le is suitable for biomarker analysis. The application of this technique further could revolutionize management of keratinocytic skin tumors by reducing the need for traditional invasive biopsy.
MC1R genotype as a predictor of early-onset melanoma, compared with self-reported and physician-measured traditional risk factors: An Australian case-control-family study
Publisher: Springer Science and Business Media LLC
Date: 04-09-2013
Genomic and Functional Approaches to Understanding Cancer Aneuploidy
Publisher: Elsevier BV
Date: 04-2018
Hepatic technetium Tc 99m?labeled sestamibi elimination rate and () genotype as indicators of ABCB1 (P-glycoprotein) activity in patients with cancer
Publisher: Springer Science and Business Media LLC
Date: 2005
DOI: 10.1016/J.CLPT.2004.09.002
Abstract: The adenosine triphosphate-binding cassette transporter ABCB1 (P-glycoprotein) mediates terminal excretion of many chemotherapeutic agents, and variable ABCB1 activity may be an important contributor to interpatient variability in the clearance of chemotherapeutic agents. Our objective was to determine the elimination constant (kH) for hepatic elimination of technetium Tc 99m-labeled sestamibi (99mTc-MIBI) in patients with cancer and to compare this putative indicator of ABCB1 phenotype with clinical features and common ABCB1 genetic variants. 99mTc-MIBI kH was determined from the time-dependent elimination profile of 99mTc-MIBI over a 90-minute hepatic scanning period in 66 patients with cancer. Single nucleotide polymorphisms (SNPs) in ABCB1 exons 12 (C1236T), 21 (G2677T/A), and 26 (C3435T) were documented by polymerase chain reaction-restriction fragment length polymorphism analysis. There was a 12-fold variation in 99mTc-MIBI kH across the cohort, which was not correlated with sex, age, conventional liver function test results, previous chemotherapy treatment, or history of liver metastasis. Mean 99mTc-MIBI kH was significantly reduced in patients with SNPs in exons 21 and 26 such that mean 99mTc-MIBI kH was 1.90 times (95% confidence interval, 1.14-2.66 P = .02) and 2.21 times (95% confidence interval, 1.47-2.97 P < .01) higher in subjects homozygous for the wild-type alleles than in those homozygous for these SNPs, respectively. Hepatic elimination of 99mTc-MIBI is a potential in vivo probe of hepatic ABCB1 activity that is significantly associated with the presence of common SNPs in ABCB1. 99mTc-MIBI hepatic scanning may provide a useful pretreatment indicator of ABCB1-mediated drug clearance in cancer patients.
Responses to ultraviolet-B in cell lines from hereditary melanoma kindreds
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2001
DOI: 10.1097/00008390-200102000-00001
Abstract: Ultraviolet-B (UV-B) triggers a cascade of events involving cell cycle control genes leading ultimately to DNA repair or apoptosis. The hypothesis examined here is that the genetic abnormality predisposing to melanoma affects the ability of the cell to respond appropriately to UV-B, so favouring mutagenesis. Epstein-Barr virus-transformed lymphoblastoid cell lines from hereditary melanoma kindreds were irradiated with UV-B, and changes in p53, p21 and Bcl-2 expression and cell cycle phase distribution were analysed. Twenty-two cell lines were tested: 12 carriers of melanoma susceptibility and 10 non-carriers (unaffected first degree relatives). At 24 h after irradiation with 50 J/m2, 15 of the 22 cell lines showed a rise in G2/M. After 400 J/m2, all the cell lines showed a reduction or loss of G2/M and 17 of the 22 showed an S phase delay. More carriers than noncarriers of melanoma susceptibility showed significant S phase delay after 50 J/m2 (seven out of 12 carriers versus two out of 10 non-carriers). Six of the 10 pairs (carrier versus non-carrier) tested showed discordant cell cycle responses however the nature of the difference was not universal. Bcl-2 reduction was seen 4 h post-irradiation in all the carriers and non-carriers. The p53 and p21 responses, although showing some in idual variations, were not related to carrier status. These results show in idual variations in response to UV-B irradiation among cell lines from the members of hereditary melanoma kindreds, but no consistent differences between carriers and non-carriers of melanoma susceptibility.
“Melanoma: Questions and Answers.” Development and evaluation of a psycho-educational resource for people with a history of melanoma
Publisher: Springer Science and Business Media LLC
Date: 27-07-2016
DOI: 10.1007/S00520-016-3339-3
Abstract: People with melanoma often report pervasive fears about cancer recurrence, unmet information needs, and difficulties accessing psychological care. Interventions addressing the supportive care needs of people with melanoma are rare, and needs are often overlooked. The study evaluated a newly developed, evidence-based, psycho-educational resource for people with melanoma. The evaluation study comprised three groups: adults at high risk of new primary disease due to multiple previous melanomas or one melanoma and dysplastic nevus syndrome (DNS), adults at moderate risk due to one previous melanoma and no DNS, and health professionals involved in melanoma care. Participants evaluated a 68-page psycho-educational booklet, Melanoma: Questions and Answers, developed by a multidisciplinary team in accordance with published evidence, clinical guidelines, and intervention development frameworks. The booklet comprised seven modules featuring information on melanoma diagnosis, treatment, prognosis, and ongoing clinical management risk factors and the role of genetic counseling services for melanoma psycho-education on emotional, behavioral, and cognitive responses to melanoma, including psycho-education on fear of cancer recurrence description of healthy coping responses a suite of tailored tools to support skin self-examination, doctor-patient communication, and identification of the signs and symptoms of anxiety and depression a list of community-based services and resources and tools to support melanoma-related record keeping and monitoring. Resource acceptability, relevance, quality, dissemination preferences, emotional responses, unmet information needs, and demographic characteristics were assessed. Nineteen melanoma survivors (response rate 50 %) and 10 health professionals (response rate 83 %) evaluated the resource. Responses were overwhelmingly positive the booklet was thoroughly read and highly rated in terms of quality and quantity of information, utility of health education tools, and capacity to address unmet needs. Ninety-five percent of melanoma survivors would recommend the booklet to others. Most preferred a paper-based format, provided by their treating doctor at diagnosis. Melanoma: Questions and Answers was feasible and acceptable and demonstrated a strong capacity to address the information and psycho-educational needs of people with melanoma at low fiscal cost.
Determination of prognosis in metastatic melanoma through integration of clinico-pathologic, mutation, mRNA, microRNA, and protein information
Publisher: Wiley
Date: 24-07-2015
DOI: 10.1002/IJC.29047
Abstract: In patients with metastatic melanoma, the identification and validation of accurate prognostic biomarkers will assist rational treatment planning. Studies based on "-omics" technologies have focussed on a single high-throughput data type such as gene or microRNA transcripts. Occasionally, these features have been evaluated in conjunction with limited clinico-pathologic data. With the increased availability of multiple data types, there is a pressing need to tease apart which of these sources contain the most valuable prognostic information. We evaluated and integrated several data types derived from the same tumor specimens in AJCC stage III melanoma patients-gene, protein, and microRNA expression as well as clinical, pathologic and mutation information-to determine their relative impact on prognosis. We used classification frameworks based on pre-validation and bootstrap multiple imputation to compare the prognostic power of each data source, both in idually as well as integratively. We found that the prognostic utility of clinico-pathologic information was not out-performed by any of the various "-omics" platforms. Rather, a combination of clinico-pathologic variables and mRNA expression data performed best. Furthermore, a patient-based classification analysis revealed that the prognostic accuracy of various data types was not the same for different patients. This indicates that ongoing development in the in idualized evaluation of melanoma patients must take account of the value of both traditional and novel "-omics" measurements.
Clinical Features Associated With Individuals at Higher Risk of Melanoma: A Population-Based Study
Publisher: American Medical Association (AMA)
Date: 2017
DOI: 10.1001/JAMADERMATOL.2016.3327
Abstract: The identification of a subgroup at higher risk of melanoma may assist in early diagnosis. To characterize melanoma patients and the clinical features associated with their melanomas according to patient risk factors: many nevi, history of previous melanoma, and family history of melanoma, to assist with improving the identification and treatment of a higher-risk subgroup. The Melanoma Patterns of Care study was a population-based observational study of physicians' reported treatment of 2727 patients diagnosed with an in situ or invasive primary melanoma over a 12-month period from October 2006 to 2007 conducted in New South Wales. Our analysis of these data took place from 2015 to 2016. Age at diagnosis and body site of melanoma. Of the 2727 patients with melanoma included, 1052 (39%) were defined as higher risk owing to a family history of melanoma, multiple primary melanomas, or many nevi. Compared with patients with melanoma who were at lower risk (ie, without any of these risk factors), the higher-risk group had a younger mean age at diagnosis (62 vs 65 years, P < .001), but this differed by risk factor (56 years for patients with a family history, 59 years for those with many nevi, and 69 years for those with a previous melanoma). These age differences were consistent across all body sites. Among higher-risk patients, those with many nevi were more likely to have melanoma on the trunk (41% vs 29%, P < .001), those with a family history of melanoma were more likely to have melanomas on the limbs (57% vs 42%, P < .001), and those with a personal history were more likely to have melanoma on the head and neck (21% vs 15%, P = .003). These findings suggest that a person's risk factor status could be used to tailor surveillance programs and education about skin self-examination.
Supplementary Data from Distinct Molecular Profiles and Immunotherapy Treatment Outcomes of V600E and V600K <i>BRAF</i>-Mutant Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22467960.V1
Abstract: Supplementary Tables 1-2, and Figures 1-5.
Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes.
Publisher: American Association for Cancer Research (AACR)
Date: 13-09-2022
DOI: 10.1158/2159-8290.CD-22-0603
Abstract: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. This article is highlighted in the In This Issue feature, p. 2711
Heritable DNA methylation marks associated with susceptibility to breast cancer
Publisher: Springer Science and Business Media LLC
Date: 28-02-2018
DOI: 10.1038/S41467-018-03058-6
Abstract: Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA s les provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case–control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541638
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Economic evaluations of psychosocial interventions in cancer: a systematic review
Publisher: Wiley
Date: 26-01-2016
DOI: 10.1002/PON.4075
Abstract: Although the effectiveness of many psychosocial interventions for people with cancer has been established, one barrier to implementation in routine clinical care is a lack of data on cost-effectiveness. We conducted a systematic review to assess the cost-effectiveness of psychosocial interventions for improving psychological adjustment among people with cancer. A systematic review of the literature, study appraisal and narrative synthesis. Eight studies involving 1668 patients were identified. Four of these reported outcomes in a cost per quality adjusted life year (QALY) framework. Six studies reported psychosocial interventions to be cost-effective for improving health-related quality of life, mood, pain, distress or fear of cancer progression, compared with usual care. Of the six psychosocial interventions identified as cost-effective, three were cognitive-behavioural therapy-based interventions, one was a nurse-delivered telephone follow-up plus educational group programme, one was a group-based exercise and psychosocial intervention and one was a series of 10 face-to-face or telephone-based in idual support sessions delivered by a nurse. The quality of studies assessed according to the Consensus Health Economic Criteria-list criteria was good overall however, some studies were limited by their choice of outcome measure and omission of important categories of costs. Several psychosocial interventions, particularly those based on cognitive-behavioural therapy, have been demonstrated to represent good value for money in cancer care. Future research should include a clear definition of the economic question, inclusion of all relevant costs, and consideration of utility-based quality of life measures for QALY estimation. Copyright © 2016 John Wiley & Sons, Ltd.
A dual antigen ELISA allows the assessment of SARS-CoV-2 antibody seroprevalence in a low transmission setting
Publisher: Cold Spring Harbor Laboratory
Date: 14-09-2020
DOI: 10.1101/2020.09.09.20191031
Abstract: Estimates of seroprevalence of SARS-CoV-2 antibodies have been h ered by inadequate assay sensitivity and specificity. Using an ELISA-based approach to that combines data about IgG responses to both the Nucleocapsid and Spike-receptor binding domain antigens, we show that near-optimal sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (0 to 0.72%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay.
Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.CCELL.2021.11.012
Abstract: We concurrently examine the whole genome, transcriptome, methylome, and immune cell infiltrates in baseline tumors from 77 patients with advanced cutaneous melanoma treated with anti-PD-1 with or without anti-CTLA-4. We show that high tumor mutation burden (TMB), neoantigen load, expression of IFNγ-related genes, programmed death ligand expression, low PSMB8 methylation (therefore high expression), and T cells in the tumor microenvironment are associated with response to immunotherapy. No specific mutation correlates with therapy response. A multivariable model combining the TMB and IFNγ-related gene expression robustly predicts response (89% sensitivity, 53% specificity, area under the curve [AUC], 0.84) tumors with high TMB and a high IFNγ signature show the best response to immunotherapy. This model validates in an independent cohort (80% sensitivity, 59% specificity, AUC, 0.79). Except for a JAK3 loss-of-function mutation, for patients who did not respond as predicted there is no obvious biological mechanism that clearly explained their outlier status, consistent with intratumor and intertumor heterogeneity in response to immunotherapy.
Genome-wide association study identifies novel breast cancer susceptibility loci
Publisher: Springer Science and Business Media LLC
Date: 28-06-2007
DOI: 10.1038/NATURE05887
The chromatin remodelling factor BRG1 is a novel binding partner of the tumor suppressor p16INK4a
Publisher: Springer Science and Business Media LLC
Date: 2009
Identification, Review, and Systematic Cross-Validation of microRNA Prognostic Signatures in Metastatic Melanoma
Publisher: Elsevier BV
Date: 2016
DOI: 10.1038/JID.2015.355
Purification and Characterization of Recombinant Mouse and Herpes Simplex Virus Ribonucleotide Reductase R2 Subunit
Publisher: American Chemical Society (ACS)
Date: 19-02-1991
DOI: 10.1021/BI00221A030
Abstract: Overexpression of recombinant mouse and herpes simplex virus ribonucleotide reductase small subunit (protein R2) has been obtained by using the T7 RNA polymerase expression system. Both proteins, which constitute about 30% of the soluble Escherichia coli proteins, have been purified to homogeneity by a rapid and simple procedure. At this stage, few of the molecules contain the iron-tyrosyl free-radical center necessary for activity however, addition of ferrous iron and oxygen under controlled conditions resulted in a mouse R2 protein containing 0.8 radical and 2 irons per polypeptide chain. In this reaction, one oxygen molecule was needed to generate each tyrosyl radical. Both proteins had full enzymatic activity. EPR spectroscopy showed that iron-center/radical interactions are considerably stronger in both mouse and viral proteins than in E. coli protein R2. CD spectra showed that the bacterial protein contains 70% alpha-helical structure compared to only about 50% in the mouse and viral proteins. Light absorption spectra between 310 and 600 nm indicate close similarity of the mu-oxo-bridged binuclear iron centers in all three R2 proteins. Furthermore, the paramagnetically shifted iron ligand proton NMR resonances show that the antiferromagnetic coupling and ligand arrangement in the iron center are nearly identical in all three species.
EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer
Publisher: Springer Science and Business Media LLC
Date: 06-08-2003
CYP3A7*1C allele
Publisher: Springer Science and Business Media LLC
Date: 26-01-2021
DOI: 10.1038/S41416-020-01185-W
Abstract: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. For pregnanediol-3-glucuronide, there were no genome-wide significant associations for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10 –18 ) in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10 –8 ). The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
Sensitivity of Preference-Based Quality-of-Life Measures for Economic Evaluations in Early-Stage Melanoma
Publisher: American Medical Association (AMA)
Date: 2018
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541635
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Development and pilot testing of an online screening decision aid for men with a family history of prostate cancer
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.PEC.2010.05.025
Abstract: This study aimed to develop and pilot test an online screening decision aid (DA) for men with a family history of prostate cancer. Eligible men (with no previous prostate cancer diagnosis) were recruited through relatives attending a urology outpatient clinic. Men evaluated the DA in two stages. First, they appraised a paper-based version using a questionnaire (n=22). Second, the same men were asked to reflect on an interactive web-based version via a semi-structured telephone interview (n=20). Men evaluated both forms of the DA positively. Of the paper-based version, the majority of participants found the DA useful (91%), and that it contained enough information to make a screening decision (73%). All participants reported that the online DA was easy to use and navigate. Most participants reported that a website was their preferred mode of receiving prostate cancer screening information (70%). The developed DA may represent the first online decision-making tool designed specifically for men with a family history prostate cancer that presents age and risk specific information to the user. Comprehensive evaluations of the efficacy and impact of educational interventions such as this are crucial to improve services for in iduals making informed screening decisions.
The Immune Landscape of Cancer
Publisher: Elsevier BV
Date: 04-2018
Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity
Publisher: Springer Science and Business Media LLC
Date: 16-10-2020
DOI: 10.1038/S41467-020-18988-3
Abstract: To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS , NF1 , NOTCH2 , PTEN and TYRP1 . Mutations and lification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with lification of TERT , CDK4 , MDM2 , CCND1 , PAK1 and GAB2 , indicating potential therapeutic options.
IGFBP7 is not required for B-RAF-induced melanocyte senescence
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.CELL.2010.04.021
Abstract: Induction of senescence permanently restricts cellular proliferation after oncogenic stimulation thereby acting as a potent barrier to tumor development. The relevant effector proteins may therefore be fundamental to cancer development. A recent study identified IGFBP7 as a secreted factor mediating melanocyte senescence induced by oncogenic B-RAF, which is found commonly in cutaneous nevi. In contrast to the previous report, we demonstrate that B-RAF signaling does not induce IGFBP7 expression, nor the expression of the IGFBP7 targets, BNIP3L, SMARCB1, or PEA15, in human melanocytes or fibroblasts. We also found no correlation between B-RAF mutational status and IGFBP7 protein expression levels in 22 melanoma cell lines, 90 melanomas, and 46 benign nevi. Furthermore, using a lentiviral silencing strategy we show that B-RAF induces senescence in melanocytes and fibroblasts, irrespective of the presence of IGFBP7. Therefore, we conclude that the secreted protein IGFBP7 is dispensable for B-RAF(V600E)-induced senescence in human melanocytes.
Identification of TFG (TRK-fused gene) as a putative metastatic melanoma tumor suppressor gene
Publisher: Wiley
Date: 17-01-2012
DOI: 10.1002/GCC.21932
Abstract: High density SNP arrays can be used to identify DNA copy number changes in tumors such as homozygous deletions of tumor suppressor genes and focal lifications of oncogenes. Illumina Human CNV370 Bead chip arrays were used to assess the genome for unbalanced chromosomal events occurring in 39 cell lines derived from stage III metastatic melanomas. A number of genes previously recognized to have an important role in the development and progression of melanoma were identified including homozygous deletions of CDKN2A (13 of 39 s les), CDKN2B (10 of 39), PTEN (3 of 39), PTPRD (3 of 39), TP53 (1 of 39), and lifications of CCND1 (2 of 39), MITF (2 of 39), MDM2 (1 of 39), and NRAS (1 of 39). In addition, a number of focal homozygous deletions potentially targeting novel melanoma tumor suppressor genes were identified. Because of their likely functional significance for melanoma progression, FAS, CH25H, BMPR1A, ACTA2, and TFG were investigated in a larger cohort of melanomas through sequencing. Nonsynonymous mutations were identified in BMPR1A (1 of 43), ACTA2 (3 of 43), and TFG (5 of 103). A number of potentially important mutation events occurred in TFG including the identification of a mini mutation "hotspot" at amino acid residue 380 (P380S and P380L) and the presence of multiple mutations in two melanomas. Mutations in TFG may have important clinical relevance for current therapeutic strategies to treat metastatic melanoma.
Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor
Publisher: Springer Science and Business Media LLC
Date: 04-03-2013
DOI: 10.1038/ONC.2013.45
Abstract: Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAF(V600E) is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAF(V600E) signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B-RAF(V600E) activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of STAT3 activity disrupted B-RAF(V600E)-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that STAT3 has a central role in the survival and contributes to chemoresistance of B-RAF(V600E) melanoma.
Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk
Publisher: Elsevier BV
Date: 11-2020
Population-based, case-control-family design to investigate genetic and environmental influences on melanoma risk
Publisher: Oxford University Press (OUP)
Date: 03-11-2009
DOI: 10.1093/AJE/KWP307
A High-Throughput Panel for Identifying Clinically Relevant Mutation Profiles in Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 04-2012
DOI: 10.1158/1535-7163.MCT-11-0676
Abstract: Success with molecular-based targeted drugs in the treatment of cancer has ignited extensive research efforts within the field of personalized therapeutics. However, successful application of such therapies is dependent on the presence or absence of mutations within the patient's tumor that can confer clinical efficacy or drug resistance. Building on these findings, we developed a high-throughput mutation panel for the identification of frequently occurring and clinically relevant mutations in melanoma. An extensive literature search and interrogation of the Catalogue of Somatic Mutations in Cancer database identified more than 1,000 melanoma mutations. Applying a filtering strategy to focus on mutations amenable to the development of targeted drugs, we initially screened 120 known mutations in 271 s les using the Sequenom MassARRAY system. A total of 252 mutations were detected in 17 genes, the highest frequency occurred in BRAF (n = 154, 57%), NRAS (n = 55, 20%), CDK4 (n = 8, 3%), PTK2B (n = 7, 2.5%), and ERBB4 (n = 5, 2%). Based on this initial discovery screen, a total of 46 assays interrogating 39 mutations in 20 genes were designed to develop a melanoma-specific panel. These assays were distributed in multiplexes over 8 wells using strict assay design parameters optimized for sensitive mutation detection. The final melanoma-specific mutation panel is a cost effective, sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular-based therapeutics for the treatment of melanoma. When used in a clinical research setting, the panel may rapidly and accurately identify potentially effective treatment strategies using novel or existing molecularly targeted drugs. Mol Cancer Ther 11(4) 888–97. ©2012 AACR.
Clinical practice guidelines for identification, screening and follow-up of individuals at high risk of primary cutaneous melanoma: a systematic review
Publisher: Oxford University Press (OUP)
Date: 11-12-2015
DOI: 10.1111/BJD.13403
Abstract: Understanding how in iduals at high-risk of primary cutaneous melanoma are best identified, screened and followed up will help optimize melanoma prevention strategies and clinical management. We conducted a systematic review of international clinical practice guidelines and documented the quality of supporting evidence for recommendations for clinical management of in iduals at high risk of melanoma. Guidelines published between January 2000 and July 2014 were identified from a systematic search of Medline, Embase and four guideline databases 34 guidelines from 20 countries were included. High-risk characteristics that were consistently reported included many melanocytic naevi, dysplastic naevi, family history, large congenital naevi, and Fitzpatrick Type I and II skin types. Most guidelines identify risk factors and recommend that in iduals at high risk of cutaneous melanoma be monitored, but only half of the guidelines provide recommendations for screening based on level of risk. There is disagreement in screening and follow-up recommendations for those with an increased risk of future melanoma. High-level evidence supports long-term screening of in iduals at high risk and monitoring using dermoscopy. Evidence is low for defining screening intervals and duration of follow-up, and for skin self-examination, although education about skin self-examination is widely encouraged. Clinical practice guidelines would benefit from a dedicated section for identification, screening and follow-up of in iduals at high risk of melanoma. Guidelines could be improved with clear definitions of multiple naevi, family history and frequency of follow-up. Research examining the benefits and costs of alternative management strategies for groups at high risk will enhance the quality of recommendations.
Whole-genome landscapes of major melanoma subtypes
Publisher: Springer Science and Business Media LLC
Date: 05-2017
DOI: 10.1038/NATURE22071
Abstract: Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals erse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.
Erratum to: BCoR-L1variation and breast cancer
Publisher: Springer Science and Business Media LLC
Date: 10-2008
DOI: 10.1186/BCR2153
Histologic features of melanoma associated with CDKN2A genotype
Publisher: Elsevier BV
Date: 03-2015
Cellular blue naevus involving the urinary bladder
Publisher: Elsevier BV
Date: 12-2012
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541641
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination
Publisher: Proceedings of the National Academy of Sciences
Date: 18-08-2015
Abstract: Subpopulations of cells in a primary melanoma sometimes disseminate and establish metastases, which usually cause mortality. By sequencing tumor s les from patients with metastatic melanoma never subjected to targeted therapies, we were able to trace the genetic evolution of cells in the primary that seed metastases. We show that distinct cells in the primary depart multiple times in parallel to seed metastases, often after evolving from a common, parental cell subpopulation. Intriguingly, we also determine that single metastases can be founded by more than one cell population found in the primary cancer. These mechanisms show how profound genetic ersity arises naturally among multiple metastases, driving growth and drug resistance, but also indicate that certain mutations may distinguish cells destined to metastasize.
Online prostate cancer screening decision aid for at-risk men: A randomized trial.
Publisher: American Psychological Association (APA)
Date: 2014
DOI: 10.1037/A0034405
Abstract: This study examines the efficacy of an online screening decision aid (DA) for men with a family history of prostate cancer. Unaffected Australian men (40-79 years) with at least one affected relative completed the first online questionnaire, were randomized to read either the tailored DA (intervention) or nontailored information about prostate cancer screening (control), then completed a questionnaire postreading and 12 months later. The primary outcome was decisional conflict regarding prostate specific antigen (PSA) testing. The impact of the DA on longitudinal outcomes was analyzed by using random intercept mixed effects models. Logistic and linear regressions were used to analyze the impact of the DA on screening behavior and decision regret. Stage of decision-making was tested as a moderator for decisional conflict and decision regret. The frequency of online material access was recorded. The DA had no effect on decisional conflict, knowledge, inclination toward PSA testing, accuracy of perceived risk, or screening behavior. However, among men considering PSA testing, those who read the DA had lower decision regret compared with men who read the control materials, β = 0.34, p < .001, 95% confidence interval (CI) = [.22, .53]. This is the first study to our knowledge to evaluate the uptake and efficacy of an online screening DA among men with a family history of prostate cancer. Men who were undecided about screening at baseline benefitted from the DA, experiencing less regret 12 months later. In relation to decisional conflict, the control materials may have operated as a less complex and equally informative DA.
Conjugated ternary doped carbon dots from vitamin B derivative: Multispectral nanoprobes for targeted melanoma bioimaging and photosensitization
Publisher: Elsevier BV
Date: 2020
Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types
Publisher: Elsevier BV
Date: 04-2018
The steadily growing problem of lentigo maligna and lentigo maligna melanoma in Australia: Population‐based data on diagnosis and management
Publisher: Wiley
Date: 09-10-2019
DOI: 10.1111/AJD.12928
Abstract: There are limited population-based data documenting the incidence and management of lentigo maligna (LM) and invasive lentigo maligna melanoma (LMM). We report the data on occurrence and management of LM and LMM in an Australian population. Prospective collection of incidence and clinician-reported management of melanoma in situ (MIS n = 450, capped) and localised invasive melanoma (n = 3251) notified to the New South Wales Cancer Registry over 12-months in 2006-2007. The estimated annual incidence of all MIS was 27.0 per 100 000 (LM 12.2, non-LM MIS 5.9 and unclassified MIS 9.0). Patients with LM or LMM were on average approximately 10 years older than those with other melanoma subtypes (P < 0.001). The head and neck was the location of 59% of LM, 44% of LMM and <20% of other melanoma subtypes (P < 0.001). The majority of LM and LMM were treated only by specialists. Diagnostic partial biopsies were more frequent for LM and LMM than for other melanoma subtypes, and primary care physicians were more likely than specialists to do a punch partial biopsy than a shave biopsy. The reported median definitive excision margin for LM was 5.0 mm compared with 7.2 mm for non-LM MIS (P = 0.001). In this Australian population, LM was twice as frequent as other types of MIS. Improved strategies for diagnosis and management are required.
Familial concordance of breast cancer pathology as an indicator of genotype in multiple-case families
Publisher: Wiley
Date: 02-09-2010
DOI: 10.1002/GCC.20816
Abstract: The heterogeneity of multiple case breast cancer families that do not carry mutations in BRCA1 or BRCA2 (non-BRCA1/2 families) poses a challenge to the identification of breast cancer susceptibility genes. The aim of this study was to determine whether intrafamilial concordance in breast cancer pathology could identify subgroups of non-BRCA1/2 families with consistent genotypic features. Invasive breast cancers were reviewed from 84 in iduals belonging to 30 multiple-case families BRCA1 (n = 9), BRCA2 (n = 10), and non-BRCA1/2 (n = 11). Hierarchical cluster analysis based on histopathology and age at first diagnosis was then used to specify three subgroups designated Clusters 1-3. The genomic features of non-BRCA1/2 families were examined by genome wide linkage and FGFR2 SNP genotyping, according to whether they showed cluster-concordant or cluster-mixed familial pathology. The majority of pathogenic BRCA1 mutation carriers (80%) fell into a single cluster. In contrast pathogenic BRCA2 mutation carriers were distributed across all three clusters and within families, cluster groups were also generally mixed. Most non-BRCA1/2 mutation carriers belonged to Cluster 3 (71%). Genome wide linkage data from five non-BRCA1/2 Cluster 3-concordant families were compared with four mixed cluster non-BRCA1/2 families. This revealed a number of distinct linkage peaks, including some regions previously associated with breast cancer susceptibility. The distribution of low risk alleles in FGFR2 was not different between these two subgroups (P = 0.237). The pattern of breast cancer pathology concordance amongst family members may assist the investigation of breast cancer susceptibility in multiple case families.
PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2016
DOI: 10.1158/1078-0432.CCR-15-1714
Abstract: Purpose: Understanding why some melanomas test negative for PD-L1 by IHC may have implications for the application of anti-PD-1 therapies in melanoma management. This study sought to determine somatic mutation and gene expression patterns associated with tumor cell PD-L1 expression, or lack thereof, in stage III metastatic melanoma to better define therapeutically relevant patient subgroups. Experimental Design: IHC for PD-L1 was assessed in 52 American Joint Committee on Cancer stage III melanoma lymph node specimens and compared with specimen-matched comprehensive clinicopathologic, genomic, and transcriptomic data. Results: PD-L1–negative status was associated with lower nonsynonymous mutation (NSM) burden (P = 0.017) and worse melanoma-specific survival [HR = 0.28 (0.12–0.66), P = 0.002] in stage III melanoma. Gene set enrichment analysis identified an immune-related gene expression signature in PD-L1–positive tumors. There was a marked increase in cytotoxic T-cell and macrophage-specific genes in PD-L1–positive melanomas. CD8Ahigh gene expression was associated with better melanoma-specific survival [HR = 0.2 (0.05–0.87), P = 0.017] and restricted to PD-L1–positive stage III specimens. NF1 mutations were restricted to PD-L1–positive tumors (P = 0.041). Conclusions: Tumor negative PD-L1 status in stage III melanoma lymph node metastasis is a marker of worse patient survival and is associated with a poor immune response gene signature. Lower NSM levels were associated with PD-L1–negative status suggesting differences in somatic mutation profiles are a determinant of PD-L1–associated antitumor immunity in stage III melanoma. Clin Cancer Res 22(15) 3915–23. ©2016 AACR.
Equitable Expanded Carrier Screening Needs Indigenous Clinical and Population Genomic Data
Publisher: Elsevier BV
Date: 08-2020
Cost-Effectiveness of a Psycho-Educational Intervention Targeting Fear of Cancer Recurrence in People Treated for Early-Stage Melanoma
Publisher: Springer Science and Business Media LLC
Date: 21-06-2019
DOI: 10.1007/S40258-019-00483-6
Abstract: This study aimed to evaluate the cost effectiveness of a newly developed psycho-educational intervention to reduce fear of cancer recurrence (FCR) in early-stage melanoma patients. A within-trial cost-effectiveness and cost-utility analysis was conducted from the Australian health system perspective using data from linked Medicare records. Outcomes included FCR, measured with the severity subscale of the FCR Inventory quality-adjusted life years (QALYs) measured using the preference-based instrument, Assessment of Quality of Life-8 Dimensions (AQoL-8D) and 12-month survival. An incremental cost-effectiveness ratio (ICER) was calculated for two economic outcomes: (1) cost per additional case of 'high' FCR avoided and (2) cost per QALY gained. Means and 95% CIs around the ICER were generated from non-parametric bootstrapping with 1000 replications. A total of 151 trial participants were included in the economic evaluation. The mean cost of the psycho-educational intervention was AU$1614 per participant, including intervention development costs. The ICER per case of high FCR avoided was AU$12,903. The cost-effectiveness acceptability curve demonstrated a 78% probability of the intervention being cost effective relative to the control at a threshold of AU$50,000 per extra person avoiding FCR. The ICER per QALY gained was AU$116,126 and the probability of the intervention being cost effective for this outcome was 36% at a willingness to pay of AU$50,000 per QALY. The psycho-educational intervention reduced FCR at 12 months for people at high risk of developing another melanoma and may represent good value for money. For the QALY outcome, the psycho-educational intervention is unlikely to be cost effective at standard government willingness-to-pay levels. The trial was prospectively registered in the Australian and New Zealand Clinical Trials Registry (CTRN12613000304730).
Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma
Publisher: Oxford University Press (OUP)
Date: 13-12-2015
DOI: 10.1093/JNCI/DJU408
Comparison of whole-exome sequencing of matched fresh and formalin fixed paraffin embedded melanoma tumours: Implications for clinical decision making
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.PATHOL.2016.01.001
Abstract: The identification of recurrent driver mutations by whole-exome sequencing (WES) of fresh-frozen human cancers and the subsequent development of novel targeted therapies have recently transformed the treatment of many cancers including melanoma. In routine clinical practice, fresh-frozen tissue is rarely available and mutation testing usually needs to be carried out on archival formalin fixed, paraffin embedded (FFPE) tissue, from which DNA is typically fragmented, cross-linked and of lower quality. In this study we aimed to determine whether WES data generated from genomic DNA (gDNA) extracted from FFPE tissues can be produced reliably and of clinically-actionable standard. In this study of ten melanoma patients, we compared WES data produced from analysis of gDNA isolated from FFPE tumour tissue with that isolated from fresh-frozen tumour tissue from the same specimen. FFPE s les were sequenced using both Illumina's Nextera and NimbleGen SeqCap exome capture kits. To examine mutations between the two tissue sources and platforms, somatic mutations in the FFPE exomes were called using the matched fresh tissue sequence as a reference. Of the 10 FFPE DNA s les, seven Nextera and four SeqCap s les passed library preparation. On average, there were 5341 and 2246 variants lost in FFPE compared to matched fresh tissue utilising Nextera and SeqCap kits, respectively. In order to explore the feasibility of future clinical implementation of WES, FFPE variants in 27 genes of important clinical relevance in melanoma were assessed. The average concordance rate was 43.2% over a total of 1299 calls for the chosen genes in the FFPE DNA. For the current clinically most important melanoma mutations, 0/3 BRAF and 6/8 (75%) NRAS FFPE calls were concordant with the fresh tissue result, which was confirmed using a Sequenom OncoCarta Panel. The poor performance of FFPE WES indicates that specialised library construction to account for low quality DNA and further refinements will be necessary before this approach could be used for routine clinical decision making over currently preferred techniques.
ClassifyR: An R package for performance assessment of classification with applications to transcriptomics
Publisher: Oxford University Press (OUP)
Date: 02-2015
DOI: 10.1093/BIOINFORMATICS/BTV066
Abstract: Although a large collection of classification software packages exist in R, a new generic framework for linking custom classification functions with classification performance measures is needed. A generic classification framework has been designed and implemented as an R package in an object oriented style. Its design places emphasis on parallel processing, reproducibility and extensibility. Finally, a comprehensive set of performance measures are available to ease post-processing. Taken together, these important characteristics enable rapid and reproducible benchmarking of alternative classifiers. Availability and implementation: ClassifyR is implemented in R and can be obtained from the Bioconductor project: ackages/release/bioc/html/ClassifyR.html Contact : dario.strbenac@sydney.edu.au Supplementary information : Supplementary data are available at Bioinformatics online.
Identification of ‘Non‐Proliferating’ B16 Melanoma Cells Using Monoclonal Antibody (Ad203) Against the M1 Subunit of Ribonucleotide Reductase
Publisher: Wiley
Date: 09-1988
DOI: 10.1111/J.1365-2184.1988.TB00793.X
Abstract: Ribonucleotide reductase catalyses a critical reaction in DNA synthesis. Its M1 subunit is present during all proliferative phases of the cell cycle, but apparently not in the quiescent phase G0. We have used a monoclonal antibody (AD203) directed against the M1 subunit to distinguish immunocytochemically proliferating from non-proliferating cultured B16 mouse melanoma cells during exponential growth. The presumption that AD203 unstained cells constituted a non-proliferating fraction was tested by simultaneously counting the cells that failed to incorporate bromodeoxyuridine (BrdU) into DNA during a prolonged BrdU exposure. The proportion of cells which did not incorporate BrdU was found to correlate closely with the proportion not staining with AD203 and therefore presumably lacking the M1 subunit. The respective morphological features of AD203 stained and unstained cells were found not to differ significantly.
BRAF/NRAS wild-type melanomas have a high mutation load correlating with histologic and molecular signatures of UV damage.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2013
DOI: 10.1158/1078-0432.CCR-13-0398
Abstract: Purpose: The mutation load in melanoma is generally high compared with other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinicopathologic features. Experimental Design: DNA was extracted from 34 fresh-frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was reviewed by two dermatopathologists. Exome sequencing was conducted and mutation rates were correlated with age, sex, tumor site, and histopathologic variables. Differences in mutations between categories of solar elastosis, pigmentation, and BRAF/NRAS mutational status were investigated. Results: The average mutation rate was 12 per megabase, similar to published results in metastases. The average mutation rate in severely sun damaged (SSD) skin was 21 per Mb compared with 3.8 per Mb in non-SSD skin (P = 0.001). BRAF/NRAS wild-type (WT) tumors had a higher average mutation rate compared with BRAF/NRAS–mutant tumors (27 vs. 5.6 mutations per Mb P = 0.0001). Tandem CC& TT/GG& AA mutations comprised 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin (P = 0.0008) and in BRAF/NRAS WT tumors (P = 0.0007). Targetable and potentially targetable mutations in WT tumors, including NF1, KIT, and NOTCH1, were spread over various signaling pathways. Conclusion: Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared with BRAF- and NRAS-mutant tumors indicating multigene screening approaches and combination therapies may be required for management of these patients. Clin Cancer Res 19(17) 4589–98. ©2013 AACR.
BCoR-L1 variation and breast cancer
Publisher: Springer Science and Business Media LLC
Date: 08-2007
DOI: 10.1186/BCR1759
The Immune Landscape of Cancer
Publisher: Elsevier BV
Date: 08-2019
Australian general practitioners’ attitudes and knowledge of sentinel lymph node biopsy in melanoma management
Publisher: The Royal Australian College of General Practitioners
Date: 06-2020
Occupational sun exposure and risk of melanoma according to anatomical site.
Publisher: Wiley
Date: 29-11-2013
DOI: 10.1002/IJC.28603
Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway
Publisher: Springer Science and Business Media LLC
Date: 07-09-2015
DOI: 10.1038/NG.3382
The intronic G13964C variant in p53 is not a high-risk mutation in familial breast cancer in Australia
Publisher: Springer Science and Business Media LLC
Date: 17-07-2001
DOI: 10.1186/BCR319
Abstract: Mutations in BRCA1 and BRCA2 account for approximately 50% of breast cancer families with more than four affected cases, whereas exonic mutations in p53, PTEN, CHK2 and ATM may account for a very small proportion. It was recently reported that an intronic variant of p53--G13964C--occurred in three out of 42 (7.1%) 'hereditary' breast cancer patients, but not in any of 171 'sporadic' breast cancer control in iduals (P = 0.0003). If this relatively frequent occurrence of G13964C in familial breast cancer and absence in control in iduals were confirmed, then this would suggest that the G13964C variant plays a role in breast cancer susceptibility. We genotyped 71 familial breast cancer patients and 143 control in iduals for the G13964C variant using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis. Three (4.2% 95% confidence interval [CI] 0-8.9%) G13964C heterozygotes were identified. The variant was also identified in 5 out of 143 (3.5% 95% CI 0.6-6.4%) control in iduals without breast cancer or a family history of breast cancer, however, which is no different to the proportion found in familial cases (P = 0.9). The present study would have had 80% power to detect an odds ratio of 4.4, and we therefore conclude that the G13946C polymorphism is not a 'high-risk' mutation for familial breast cancer.
Comparison of the pandemic H1N1 2009 experience in the Southern Hemisphere with pandemic expectations
Publisher: Elsevier BV
Date: 08-2012
Diagnosis of cutaneous melanocytic tumours by four-colour fluorescence in situ hybridisation
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1080/00313020902915875
Abstract: Accurate classification of primary melanocytic tumours as benign or malignant is crucial for prognostic prediction and appropriate patient management. Several chromosomal aberrations have been frequently identified in melanomas, but are absent in melanocytic naevi. We performed four-colour fluorescence in situ hybridisation (FISH) analysis of melanocytic tumours to determine the accuracy of the technique in classifying melanocytic tumours as benign or malignant. FISH was performed on paraffin-embedded tissue from 40 histologically unequivocal melanocytic tumours (10 metastatic melanomas, 10 primary melanomas and 20 benign melanocytic naevi) using the product Vysis LSI RREB1/LSI MYB/LSI CCND1/CEP 6 probes (Abbott Molecular Laboratories, USA), which is designed to detect the copy number of the RREB1 (6p25), MYB (6q23), and CCND1 (11q13) genes and FISH positivity is defined by means of a scoring algorithm. FISH distinguished the melanomas and the naevi with a sensitivity of 90% (10/10 primary melanoma cases and 8/10 metastatic melanoma cases, respectively), and a specificity of 95%. The most common abnormalities in the melanomas were increased copies of 11q (70%) and 6p (70%), followed by 6q loss relative to cep6 (50%). Fifteen of the 18 positive melanomas were positive by more than one criterion. The results of this study show that FISH, using a panel of four probes, is a sensitive and specific method of classifying benign and malignant melanocytic tumours. The four-colour FISH technique has the potential to assist in the stratification of the subgroup of melanocytic tumours which are difficult to classify using conventional histology.
Sunbed use during adolescence and early adulthood is associated with increased risk of early-onset melanoma
Publisher: Wiley
Date: 28-07-2011
DOI: 10.1002/IJC.25576
Abstract: Sunbed use is associated with increased risk of melanoma. Younger people might be more susceptible to the carcinogenic effects of ultraviolet radiation. We investigated the association between sunbed use and risk of early‐onset cutaneous malignant melanoma. From the Australian Melanoma Family Study, a multicentre, population‐based, case‐control‐family study, we analysed data for 604 cases diagnosed between ages 18 and 39 years and 479 controls. Data were collected by interview. Associations were estimated as odds ratios (ORs) using unconditional logistic regression, adjusting for age, sex, city, education, family history, skin color, usual skin response to sunlight and sun exposure. Compared with having never used a sunbed, the OR for melanoma associated with ever‐use was 1.41 (95% confidence interval (CI) 1.01–1.96), and 2.01 (95% CI 1.22–3.31) for more than 10 lifetime sessions ( P trend 0.01 with cumulative use). The association was stronger for earlier age at first use ( P trend 0.02). The association was also stronger for melanoma diagnosed when aged 18–29 years (OR for more than 10 lifetime sessions = 6.57, 95% CI 1.41–30.49) than for melanoma diagnosed when 30–39 years (OR 1.60, 95% CI 0.92–2.77 P interaction 0.01). Among those who had ever used a sunbed and were diagnosed between 18 and 29 years of age, three quarters (76%) of melanomas were attributable to sunbed use. Sunbed use is associated with increased risk of early‐onset melanoma, with risk increasing with greater use, an earlier age at first use and for earlier onset disease.
Predictors of Vinorelbine Pharmacokinetics and Pharmacodynamics in Patients With Cancer
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2006
Abstract: Marked interin idual variation in drug disposition and toxicity pose an ongoing challenge to chemotherapy dosage in idualization. The aim of this study was to evaluate pretreatment clinical features, genotype and functional indicators of drug clearance as predictors of vinorelbine clearance, and myelotoxicity that could inform dosage optimization. Forty-one patients with cancer received a 60 mg intravenous dose of vinorelbine. Pretreatment routine body size measurements and blood tests were performed. Midazolam clearance and hepatic technetium labeled sestamibi ( 99m Tc-MIBI) clearance were used to investigate CYP3A and ABCB1 (MDR1, P-glycoprotein) phenotype respectively and selected single nucleotide polymorphisms in CYP3A and ABCB1 were documented. A limited blood s ling strategy was employed and vinorelbine concentrations were determined by high-performance liquid chromatography. Posterior Bayesian estimates of vinorelbine clearance were obtained for each patient using population pharmacokinetic modeling. Myelotoxicity was estimated from the fractional survival of neutrophils post-treatment. There was 4.3-fold variation in vinorelbine clearance across the cohort. In a multivariable analysis, pretreatment estimated creatinine clearance (P .01) and hepatic 99m Tc-MIBI clearance (P = .01) were independent predictors of vinorelbine clearance. Fractional survival of neutrophils ranged from 1.3% to 100% and was significantly correlated with vinorelbine clearance (P .01). Body-surface area was the only pretreatment predictor of fractional survival of neutrophils independent of vinorelbine clearance (P = .02). Specific indicators of drug clearance provide predictive information about vinorelbine pharmacokinetics, and body-surface area, probably reflecting normal bone marrow reserve, provides an additional pharmacodynamic indicator. Use of a fixed dose of vinorelbine with modifications guided by pretreatment measures is worthy of prospective evaluation.
Anticipated uptake of genetic testing for familial melanoma in an Australian sample: an exploratory study
Publisher: Wiley
Date: 2006
DOI: 10.1002/PON.1052
Abstract: The potential role of genetic testing in families with an inherited pattern of melanoma is a complex issue, and yet limited data exist on perceptions of predictive genetic testing for mutations among in iduals at high risk of melanoma. Forty semi-structured interviews were undertaken with affected and unaffected in iduals at either high or average risk of developing melanoma due to family history. Interviews addressed key issues such as: the role of genetics in causal attributions for melanoma genetic testing intentions and motivations perceived accuracy of genetic testing in predicting melanoma onset, and the impact of varied accuracy on testing intentions views on the testing of children perceived benefits and limitations of testing and information needs and communication preferences. In-depth thematic analysis revealed a number of important qualitative differences between groups at varying risk of melanoma, and genders. Specifically, participants with a family history of melanoma believed genetic factors play an important role in melanoma causation conveyed strong intentions to pursue genetic testing and viewed the benefits of genetic testing as outweighing the limitations. Females appeared to endorse the testing of children more firmly than males, and males' intentions to pursue testing appeared more contingent on penetrance than females'. Across groups, the most preferred communication option was an informational video. Those at high risk of melanoma due to family history express a strong interest in predictive genetic testing.
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541626.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Detection of Primary Melanoma in Individuals at Extreme High Risk A Prospective 5-Year Follow-up Study
Publisher: American Medical Association (AMA)
Date: 08-2014
DOI: 10.1001/JAMADERMATOL.2014.514
Abstract: The clinical phenotype and certain predisposing genetic mutations that confer increased melanoma risk are established however, no consensus exists regarding optimal screening for such in iduals. Early identification remains the most important intervention in reducing melanoma mortality. To evaluate the impact of full-body examinations every 6 months supported by dermoscopy and total-body photography (TBP) on all patients and sequential digital dermoscopy imaging (SDDI), when indicated, on detecting primary melanoma in an extreme-risk population. Prospective observational study from February 2006 to February 2011, with patients recruited from Sydney Melanoma Diagnostic Centre and Melanoma Institute Australia who had a history of invasive melanoma and dysplastic nevus syndrome, history of invasive melanoma and at least 3 first-degree or second-degree relatives with prior melanoma, history of at least 2 primary invasive melanomas, or a CDKN2A or CDK4 gene mutation. Six-month full-body examination compared with TBP. For equivocal lesions, SDDI short term (approximately 3 months) or long term (≥6 months), following established criteria, was performed. Atypical lesions were excised. New primary melanoma numbers, characteristics, and cumulative incidence in each patient subgroup effect of diagnostic aids on new melanoma identification. In 311 patients with a median (interquartile range [IQR]) follow-up of 3.5 (2.4-4.2) years, 75 primary melanomas were detected, 14 at baseline visit. Median (IQR) Breslow thickness of postbaseline incident melanomas was in situ (in situ to 0.60 mm). Thirty-eight percent were detected using TBP and 39% with SDDI. Five melanomas were greater than 1 mm Breslow thickness, 3 of which were histologically desmoplastic the other 2 had nodular components. The benign to malignant excision ratio was 1.6:1 for all lesions excised and 4.4:1 for melanocytic lesions. Cumulative risk of developing a novel primary melanoma was 12.7% by year 2, with new primary melanoma incidence during the final 3 years of follow-up half of that observed during the first 2 years (incidence density ratio, 0.43 [95% CI, 0.25-0.74] P = .002). Monitoring patients at extreme risk with TBP and SDDI assisted with early diagnosis of primary melanoma. Hypervigilance for difficult-to-detect thick melanoma subtypes is crucial.
Psychoeducational Intervention to Reduce Fear of Cancer Recurrence in People at High Risk of Developing Another Primary Melanoma: Results of a Randomized Controlled Trial
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-12-2016
Abstract: People with a history of melanoma commonly report a fear of cancer recurrence (FCR), yet psychologic support is not routinely offered as part of ongoing melanoma care. This randomized controlled trial examined the efficacy of a psychoeducational intervention to reduce FCR and improve psychologic adjustment in this patient group compared with usual care. The intervention comprised a newly developed psychoeducational resource and three telephone-based psychotherapeutic sessions over a 1-month period timed in accordance with dermatologic appointments. Participants were randomly assigned to intervention (n = 80) or usual care (n = 84). Assessments were completed at baseline, 1 month, and 6 months after dermatologic appointments. Linear mixed models were used to examine differences between treatment and control groups for patient-reported outcomes, including FCR, anxiety, stress, depression, melanoma-related knowledge, health behaviors, satisfaction with melanoma care, unmet needs, and health-related quality of life. At 6 months, the intervention group reported lower FCR severity, trigger, and distress scores than the control group in the baseline-adjusted models the between-group mean difference was −1.9 for FCR severity (95% CI, −3.1 to −0.7 P = .002), −2.0 for FCR triggers (95% CI, −3.3 to −0.7 P = .003), and −0.7 for FCR distress (95% CI, −1.3 to −0.1 P = .03). The decrease in FCR severity (but not triggers or distress) remained statistically significant after adjustment for other covariates ( P = .04). At 6 months, the intervention group also reported lower stress (−1.6 95% CI, −3.1 to −0.2 P = .03) and improved melanoma-related knowledge (1.7 95% CI, 0.8 to 2.6 P .001) compared with the control group. No differences were found between groups for other secondary outcomes. This newly developed evidence-based psychoeducational intervention was effective in reducing FCR and stress and increasing melanoma-related knowledge in people at high risk for another melanoma.
Improving subjective perception of personal cancer risk: systematic review and meta-analysis of educational interventions for people with cancer or at high risk of cancer
Publisher: Wiley
Date: 14-01-2014
DOI: 10.1002/PON.3476
Abstract: Newly diagnosed patients with cancer require education about the disease, the available treatments and potential consequences of treatment. Greater understanding of cancer risk has been found to be associated with greater health-related quality of life, improved psychological adjustment and greater health-related behaviours. The aim of this sytematic review was to assess the effectiveness of educational interventions in improving subjective cancer risk perception and to appraise the quality of the studies. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) and prospective observational studies. Eligible studies were identified via Medline, PsycINFO, AMED, CINAHL and Embase databases. After screening titles and abstracts, two reviewers independently assessed the eligibility of 206 full-text articles. Forty papers were included in the review the majority of studies were conducted among breast cancer patients (n = 29) and evaluated the effect of genetic counselling on personal perceived risk (n = 25). Pooled results from RCTs (n = 12) showed that, both in the short and long term, educational interventions did not significantly influence risk perception level (standardised mean difference 0.05, 95% CI -0.24-0.34 p = 0.74) or accuracy (odds ratio = 1.96, 95% CI: 0.61-6.25 p = 0.26). Only one RCT reported a short-term difference in risk ratings (p = 0.01). Of prospective observational studies (n = 28), many did demonstrate changes in the level of perceived risk and improved risk accuracy and risk ratings in both the short and long term. However, only one (of three) observational studies reported a short-term difference in risk ratings (p < = 0.003). Further development and investigation of educational interventions using good quality, RCTs are warranted.
Melanomas of unknown primary have a mutation profile consistent with cutaneous sun‐exposed melanoma
Publisher: Wiley
Date: 23-08-2013
DOI: 10.1111/PCMR.12153
Abstract: Melanoma of unknown primary (MUP) is an uncommon phenomenon whereby patients present with metastatic disease without an evident primary site. To determine their likely site of origin, we combined exome sequencing from 33 MUPs to assess the total rate of somatic mutations and degree of UV mutagenesis. An independent cohort of 91 archival MUPs was also screened for 46 hot spot mutations highly prevalent in melanoma including BRAF, NRAS, KIT, GNAQ, and GNA11. Results showed that the majority of MUPs exhibited high somatic mutation rates, high ratios of C>T/G>A transitions, and a high rate of BRAF (45 of 101, 45%) and NRAS (32 of 101, 32%) mutations, collectively indicating a mutation profile consistent with cutaneous sun-exposed melanomas. These data suggest that a significant proportion of MUPs arise from regressed or unrecognized primary cutaneous melanomas or arise de novo in lymph nodes from nevus cells that have migrated from the skin.
Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families
Publisher: Springer Science and Business Media LLC
Date: 23-04-2021
DOI: 10.1186/S12889-021-10424-5
Abstract: In iduals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. In iduals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, in iduals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.
The molecular profile of metastatic melanoma in Australia
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.PATHOL.2015.12.008
Abstract: Targeted therapy directed at driver oncogenic mutations offers an effective treatment option for select patients with metastatic melanoma. The aim of this study was to assess the prevalence of clinically significant somatic mutations, specifically BRAF, NRAS and KIT, in a large cohort of Australian patients with metastatic melanoma. We performed a cross-sectional cohort study of consecutive patients with American Joint Committee on Cancer (AJCC) stage IIIc unresectable or stage IV melanoma managed at Melanoma Institute Australia, and affiliated sites, that underwent molecular testing between 22 June 2009 and 19 July 2013. Additionally, we examined the change in BRAF testing methodology and patient population over time, and how this influenced the prevalence of mutations. A total of 767 molecular tests were conducted for 733 patients. BRAF V600 mutation testing was performed for 713 patients (97.2%), with an overall mutation prevalence of 37.7% (269/713) 74.3% (200/269) were the V600E genotype and 22.3% (60/269) V600K. The BRAF mutation prevalence and proportion of BRAF V600E and V600K genotypes varied across the study period, as did testing methodology and the median age of the cohorts. Of 222 patients who underwent NRAS testing, 58 (26.1%) had a mutation identified. The overall prevalence of KIT mutations was 3.7% (11/296). In Australia the prevalence of BRAF mutations is lower than initially reported, although this remains the most common mutation identified in metastatic melanoma and an important therapeutic target. NRAS mutations are more prevalent than initially described however, other mutations reported in melanoma, including KIT, are rare in an unselected population of patients.
The Melanoma Genomics Managing Your Risk Study randomised controlled trial: Statistical Analysis Plan
Publisher: Cold Spring Harbor Laboratory
Date: 20-04-2020
DOI: 10.1101/2020.04.13.20064246
Abstract: The Melanoma Genomics Managing Your Risk Study is a randomised controlled trial that aims to evaluate the efficacy of providing information on personal genomic risk of melanoma in reducing ultraviolet radiation (UV) exposure, stratified by traditional risk group (low or high phenotypic risk) in the general population. The primary outcome is objectively measured total daily Standard Erythemal Doses at 12 months. Secondary outcomes include UV exposure at specific time periods, self-reported sun protection and skin-examination behaviors, psychosocial outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the cost-effectiveness of the intervention. To publish the pre-determined statistical analysis plan (SAP) before database lock and the start of analysis. This SAP describes the data synthesis, analysis principles and statistical procedures for analysing the outcomes from this trial. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid potential analysis bias that may arise from knowledge of the outcome data. This SAP is consistent with best practice and will enable transparent reporting. This SAP has been developed for the Melanoma Genomics Managing Your Risk Study and will be followed to ensure high-quality standards of internal validity and to minimise analysis bias. Prospectively registered with the Australian New Zealand Clinical Trials Registry ACTRN12617000691347 (date registered: 15/05/2017).
Low prevalence of RAS-RAF-activating mutations in Spitz melanocytic nevi compared with other melanocytic lesions
Publisher: Wiley
Date: 18-05-2007
DOI: 10.1111/J.1600-0560.2006.00646.X
Abstract: Melanocytic lesions, including Spitz nevi (SN), common benign nevi (CBN) and cutaneous metastatic melanoma (CMM), were analyzed for activating mutations in NRAS, HRAS and BRAF oncogenes, which induce cellular proliferation via the MAP kinase pathway. One of 22 (4.5%) SN tested showed an HRAS G61L mutation. Another lesion, a 'halo' SN, showed a BRAF V600E (T1796A) mutation. BRAF V600E mutations were found in two thirds (20/31) of CBN, while a further 19% (6/31) showed NRAS codon 61 mutations. One third of CMM (10/30) had various BRAF mutations of codon 600, and a further 6% (2/31) showed NRAS codon 61 mutations. Seventeen SN tested for loss of heterozygosity (LOH) at 9p and 10q regions, known to be frequently deleted in melanoma, showed LOH at the 9p loci D9S942 and IFNA. A further lesion was found with low-level microsatellite instability at one locus, D10S214. The low rate of RAS-RAF mutations (2/22, 9.1%) observed in SN suggests that these lesions harbor as yet undetected activating mutations in other components of the RAS-RAF-MEK-ERK-MAPK pathway. Germline DNA from members of 111 multiple-case melanoma families, representing a range of known (CDKN2A) and unknown predisposing gene defects, was analyzed for germline BRAF mutations, but none was found.
Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma
Publisher: Springer Science and Business Media LLC
Date: 03-08-2015
DOI: 10.1038/NG.3373
Melanoma Explorer: a web application to allow easy reanalysis of publicly available and clinically annotated melanoma omics data sets
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2019
Genome-wide association study identifies novel loci predisposing to cutaneous melanoma†
Publisher: Oxford University Press (OUP)
Date: 17-09-2011
DOI: 10.1093/HMG/DDR415
Normal repair of ultraviolet radiation-induced DNA damage in familial melanoma without CDKN2A or CDK4 gene mutation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1999
DOI: 10.1097/00008390-199904000-00004
Abstract: Excessive sun exposure and family history are strong risk factors for the development of cutaneous melanoma. Inherited susceptibility to this type of skin cancer could therefore result from constitutively impaired capacity to repair ultraviolet (UV)-induced DNA lesions. While a proportion of familial melanoma kindreds exhibit germline mutations in the cell cycle regulatory gene CDKN2A (p16INK4a) or its protein target, cyclin-dependent kinase 4 (CDK4), the biochemical basis of most familial melanoma is unknown. We have examined lymphoblastoid cell lines from melanoma-affected and unaffected in iduals from large hereditary melanoma kindreds which are not attributable to CDKN2A or CDK4 gene mutation. These lines were tested for sensitivity of clonogenic growth to UV radiation and for their ability to repair transfected UV-damaged plasmid templates (host cell reactivation). Two of seven affected-unaffected pairs differed in colony survival after exposure to UVB radiation however, no significant differences were observed in the host-cell reactivation assays. These results indicate that melanoma susceptibility genes other than CDKN2A and CDK4 do not impair net capacity to repair UV-induced DNA damage.
Molecular Genomic Profiling of Melanocytic Nevi
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.JID.2018.12.033
Abstract: The benign melanocytic nevus is the most common tumor in humans and rarely transforms into cutaneous melanoma. Elucidation of the nevus genome is required to better understand the molecular steps of progression to melanoma. We performed whole genome sequencing on a series of 14 benign melanocytic nevi consisting of both congenital and acquired types. All nevi had driver mutations in the MAPK signaling pathway, either BRAF V600E or NRAS Q61R/L. No additional definite driver mutations were identified. Somatic mutations in nevi with higher mutation loads showed a predominance of mutational signatures 7a and 7b, consistent with UVR exposure, whereas nevi with lower mutation loads (including all three congenital nevi) had a predominance of the ubiquitous signatures 1 and 5. Two nevi had mutations in promoter regions predicted to bind E26 transformation-specific family transcription factors, as well as subclonal mutations in the TERT promoter. This paper presents whole genome data from melanocytic nevi. We confirm that UVR is involved in the etiology of a subset of nevi. This study also establishes that TERT promoter mutations are present in morphologically benign skin nevi in subclonal populations, which has implications regarding the interpretation of this emerging biomarker in sensitive assays.
Specialized surveillance for individuals at high risk for melanoma: a cost analysis of a high-risk clinic
Publisher: American Medical Association (AMA)
Date: 02-2015
DOI: 10.1001/JAMADERMATOL.2014.1952
Abstract: Regular surveillance of in iduals at high risk for cutaneous melanoma improves early detection and reduces unnecessary excisions however, a cost analysis of this specialized service has not been undertaken. To determine the mean cost per patient of surveillance in a high-risk clinic from the health service and societal perspectives. We used a bottom-up microcosting method to measure resource use in a consecutive s le of 102 patients treated in a high-risk hospital-based clinic in Australia during a 12-month period. Surveillance and treatment of melanoma. All surveillance and treatment procedures were identified through direct observation, review of medical records, and interviews with staff and were valued using scheduled fees from the Australian government. Societal costs included transportation and loss of productivity. The mean number of clinic visits per year was 2.7 (95% CI, 2.5-2.8) for surveillance and 3.8 (95% CI, 3.4-4.1) for patients requiring surgical excisions. The mean annual cost per patient to the health system was A $882 (95% CI, A $783-$982) (US $599 [95% CI, US $532-$665]) the cost discounted across 20 years was A $11,546 (95% CI, A $10,263-$12,829) (US $7839 [95% CI, US $6969-$8710]). The mean annual societal cost per patient (excluding health system costs) was A $972 (95% CI, A $899-$1045) (US $660 [95% CI, US $611-$710]) the cost discounted across 20 years was A $12,721 (95% CI, A $12,554-$14,463) (US $8637 [95% CI, US $8523-$9820]). Diagnosis of melanoma or nonmelanoma skin cancer and frequent excisions for benign lesions in a relatively small number of patients was responsible for positively skewed health system costs. Microcosting techniques provide an accurate cost estimate for the provision of a specialized service. The high societal cost reflects the time that patients are willing to invest to attend the high-risk clinic. This alternative model of care for a high-risk population has relevance for decision making about health policy.
A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma
Publisher: Springer Science and Business Media LLC
Date: 13-11-2011
DOI: 10.1038/NATURE10630
Overlapping genetic architecture between Parkinson disease and melanoma
Publisher: Springer Science and Business Media LLC
Date: 16-12-2020
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541638.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
A highly recurrent RPS27 5 ' UTR mutation in melanoma
Publisher: Impact Journals, LLC
Date: 30-05-2014
The Melanoma Genomics Managing Your Risk Study randomised controlled trial: statistical analysis plan.
Publisher: Springer Science and Business Media LLC
Date: 30-06-2020
DOI: 10.1186/S13063-020-04351-W
Abstract: The Melanoma Genomics Managing Your Risk Study is a randomised controlled trial that aims to evaluate the efficacy of providing information on personal genomic risk of melanoma in reducing ultraviolet radiation (UV) exposure, stratified by traditional risk group (low or high phenotypic risk) in the general population. The primary outcome is objectively measured total daily Standard Erythemal Doses at 12 months. Secondary outcomes include UV exposure at specific time periods, self-reported sun protection and skin-examination behaviours, psychosocial outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the cost-effectiveness of the intervention. To publish the pre-determined statistical analysis plan (SAP) before database lock and the start of analysis. This SAP describes the data synthesis, analysis principles and statistical procedures for analysing the outcomes from this trial. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid potential analysis bias that may arise from knowledge of the outcome data. This SAP is consistent with best practice and should enable transparent reporting. This SAP has been developed for the Melanoma Genomics Managing Your Risk Study and will be followed to ensure high-quality standards of internal validity and to minimise analysis bias. Prospectively registered with the Australian New Zealand Clinical Trials Registry, ID: ACTR N12617000691347 . Registered on 15 May 2017.
Localization of a Novel Melanoma Susceptibility Locus to 1p22
Publisher: Elsevier BV
Date: 08-2003
DOI: 10.1086/377140
Abstract: Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82 recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores >3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.
Variation in the RAD51 gene and familial breast cancer
Publisher: Springer Science and Business Media LLC
Date: 06-2006
DOI: 10.1186/BCR1415
Mechanisms determining sensitivity to cisplatin in three mutant Chinese hamster ovary cell lines
Publisher: Elsevier BV
Date: 06-1998
DOI: 10.1016/S0921-8777(98)00006-8
Abstract: To gain insight into factors determining the response of tumours to cisplatin, we studied pathways involved in resistance to cisplatin: drug uptake, cytoplasmic detoxification and DNA repair, in three cisplatin-sensitive Chinese hamster ovary (CHO)2 mutant cell lines. The mutant lines, CHO-MMC6, CHO-MMC1, CHO-MMS2, displayed inherent sensitivity to cisplatin (2.2, 4.1 and 10.6-fold, respectively) compared to the CHO-K1 line from which they were derived. CHO-MMS2 was the only mutant to show sensitivity to UV and this was slight (< 2-fold). None of the mutants displayed increased sensitivity to X-irradiation. The CHO-MMS2 cell line appeared to have multiple mechanisms involved in its sensitivity to cisplatin, including increased drug accumulation, decreased levels of glutathione and a decreased capacity for DNA repair. The CHO-MMC1 mutant demonstrated reduced ability for DNA repair in a host cell reactivation assay, but no difference in drug accumulation or glutathione levels compared to the parent. The CHO-MMC6 cell line was not defective in any of the mechanisms studied. These three mutant cell lines demonstrate that similar mechanisms may account for inherent sensitivity or resistance to cisplatin, and suggest that multiple mechanisms may determine the sensitivity of human tumours to cisplatin.
Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines
Publisher: Elsevier BV
Date: 03-2018
Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas
Publisher: Elsevier BV
Date: 03-2018
Intronic sequence variants of the CDKN2A gene in melanoma pedigrees
Publisher: Wiley
Date: 10-03-2005
DOI: 10.1002/GCC.20177
Abstract: Germ-line mutations of the tumor-suppressor gene CDKN2A predispose in iduals to melanoma in families worldwide. However, coding mutations of CDKN2A have not been detected in a significant proportion of those affected. The identification of a disease-associated intronic mutation of CDKN2A in UK families, which has proved to be the most common CDKN2A mutation as yet identified in this population, has highlighted the possibility that additional causal mutations may lie within the intronic sequence of the gene. In this article, we describe the comprehensive screening of 109 English and 26 Australian melanoma pedigrees for intronic mutations of CDKN2A. In total, 24 sequence variants were identified across the two introns of the gene. We show evidence that two of the CDKN2A intronic variants (IVS1 + 1104 C > A and IVS1 - 1104 C > G) predispose to melanoma. IVS1 + 1104 was shown to result in the aberrant splicing of both p16(INK4a) and p14(ARF) mRNA. Overall, however, the proportion of English melanoma families with these variants is small.
Deletion mapping suggests that the 1p22 melanoma susceptibility gene is a tumor suppressor localized to a 9-Mb interval
Publisher: Wiley
Date: 19-05-2004
DOI: 10.1002/GCC.20056
Abstract: Loss of the short arm of chromosome 1 is frequently observed in many tumor types, including melanoma. We recently localized a third melanoma susceptibility locus to chromosome band 1p22. Critical recombinants in linked families localized the gene to a 15-Mb region between D1S430 and D1S2664. To map the locus more finely we have performed studies to assess allelic loss across the region in a panel of melanomas from 1p22-linked families, sporadic melanomas, and melanoma cell lines. Eighty percent of familial melanomas exhibited loss of heterozygosity (LOH) within the region, with a smallest region of overlapping deletions (SRO) of 9 Mb between D1S207 and D1S435. This high frequency of LOH makes it very likely that the susceptibility locus is a tumor suppressor. In sporadic tumors, four SROs were defined. SRO1 and SRO2 map within the critical recombinant and familial tumor region, indicating that one or the other is likely to harbor the susceptibility gene. However, SRO3 may also be significant because it overlaps with the markers with the highest 2-point LOD score (D1S2776), part of the linkage recombinant region, and the critical region defined in mesothelioma. The candidate genes PRKCL2 and GTF2B, within SRO2, and TGFBR3, CDC7, and EVI5, in a broad region encompassing SRO3, were screened in 1p22-linked melanoma kindreds, but no coding mutations were detected. Allelic loss in melanoma cell lines was significantly less frequent than in fresh tumors, indicating that this gene may not be involved late in progression, such as in overriding cellular senescence, necessary for the propagation of melanoma cells in culture.
Protein signatures correspond to survival outcomes of AJCC stage III melanoma patients
Publisher: Wiley
Date: 14-08-2014
DOI: 10.1111/PCMR.12290
Driver Fusions and Their Implications in the Development and Treatment of Human Cancers
Publisher: Elsevier BV
Date: 04-2018
Men's preferences and trade-offs for prostate cancer screening: A discrete choice experiment
Publisher: Wiley
Date: 10-11-2015
DOI: 10.1111/HEX.12301
p16INK4a Expression and Absence of Activated B-RAF Are Independent Predictors of Chemosensitivity in Melanoma Tumors
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1593/NEO.08702
Abstract: Metastatic cutaneous melanoma is highly resistant to cytotoxic drugs, and this contributes to poor prognosis. In vivo studies on the chemosensitivity of metastatic melanoma are rare and h ered by poor response rates to systemic chemotherapeutics. Patients who undergo isolated limb infusion (ILI) with cytotoxic drugs show high response rates and are, therefore, a good cohort for studying chemosensitivity in vivo. We used tumors from patients who underwent ILI to study the role of melanoma tumor-suppressor genes and oncogenes on melanoma chemosensitivity. Prospectively acquired tumors from 30 patients who subsequently underwent ILI with melphalan and actinomycin-D for metastatic melanoma were investigated for mRNA expression levels of p14(ARF), p16(INK4a), and MITFm. The mutation status of B-RAF, N-RAS, and PTEN were also determined. A high percentage of tumors had activating mutations in either B-RAF (15/30) or N-RAS (10/30) and only two tumors carried altered PTEN. High expression of p16(INK4a) and absence of an activating B-RAF mutation independently predicted response to treatment. Further, inducible expression of p16(INK4a) sensitized a melanoma cell line to death induced by melphalan or actinomycin-D. This study shows that high expression of p16(INK4a) or the absence of activated B-RAF correlates with in vivo response of melanoma to cytotoxic drugs.
Sunscreen use and melanoma risk among young Australian adults
Publisher: American Medical Association (AMA)
Date: 09-2018
Assessing the Incremental Contribution of Common Genomic Variants to Melanoma Risk Prediction in Two Population-Based Studies
Publisher: Elsevier BV
Date: 12-2018
Network-based biomarkers enhance classical approaches to prognostic gene expression signatures
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Association between putative functional variants in the PSMB 9 gene and risk of melanoma – re‐analysis of published melanoma genome‐wide association studies
Publisher: Wiley
Date: 27-03-2013
DOI: 10.1111/PCMR.12069
Melanoma survivors at high risk of developing new primary disease: a qualitative examination of the factors that contribute to patient satisfaction with clinical care
Publisher: Wiley
Date: 05-02-2013
DOI: 10.1002/PON.3243
Abstract: Providing ongoing clinical care that adequately addresses patients' medical, psychosocial and information needs is challenging, particularly for patient groups at increased risk of developing life-threatening disease such as malignant melanoma. This study examined a model of clinical care developed by the High Risk Clinic (HRC) of the Sydney Melanoma Diagnostic Centre in relation to patient satisfaction. Semi-structured telephone interviews were conducted and analyzed using the framework of Miles and Huberman, and themes were organized using the qualitative software package, QSR NVivo8. Twenty HRC patients participated in the study (nine men, 11 women mean age 57.6 years, age range 34-74 years response rate 91%). Satisfaction with clinical care at the HRC was high. Factors contributing to patient satisfaction included: rapid and regular access to physicians who were perceived by participants as experts, the development of confidence and trust in one's treating doctor, and a sense of being cared about and understood by one's healthcare team. Although one-third of the participants reported some inconveniences in attending the clinic, these were viewed as minor difficulties and not significant barriers to care. Formal psychological support was not sought or expected by participants, although many expressed long-standing melanoma-related fears and concerns. Accessible, expert medical attention, delivered in a patient-centered manner was integral to melanoma survivors' satisfaction with clinical management. Appropriate referrals to psychological support may further increase satisfaction with clinical care.
Development and external validation of a melanoma risk prediction model based on self-assessed risk factors
Publisher: American Medical Association (AMA)
Date: 08-2016
DOI: 10.1001/JAMADERMATOL.2016.0939
Abstract: Identifying in iduals at high risk of melanoma can optimize primary and secondary prevention strategies. To develop and externally validate a risk prediction model for incident first-primary cutaneous melanoma using self-assessed risk factors. We used unconditional logistic regression to develop a multivariable risk prediction model. Relative risk estimates from the model were combined with Australian melanoma incidence and competing mortality rates to obtain absolute risk estimates. A risk prediction model was developed using the Australian Melanoma Family Study (629 cases and 535 controls) and externally validated using 4 independent population-based studies: the Western Australia Melanoma Study (511 case-control pairs), Leeds Melanoma Case-Control Study (960 cases and 513 controls), Epigene-QSkin Study (44 544, of which 766 with melanoma), and Swedish Women's Lifestyle and Health Cohort Study (49 259 women, of which 273 had melanoma). We validated model performance internally and externally by assessing discrimination using the area under the receiver operating curve (AUC). Additionally, using the Swedish Women's Lifestyle and Health Cohort Study, we assessed model calibration and clinical usefulness. The risk prediction model included hair color, nevus density, first-degree family history of melanoma, previous nonmelanoma skin cancer, and lifetime sunbed use. On internal validation, the AUC was 0.70 (95% CI, 0.67-0.73). On external validation, the AUC was 0.66 (95% CI, 0.63-0.69) in the Western Australia Melanoma Study, 0.67 (95% CI, 0.65-0.70) in the Leeds Melanoma Case-Control Study, 0.64 (95% CI, 0.62-0.66) in the Epigene-QSkin Study, and 0.63 (95% CI, 0.60-0.67) in the Swedish Women's Lifestyle and Health Cohort Study. Model calibration showed close agreement between predicted and observed numbers of incident melanomas across all deciles of predicted risk. In the external validation setting, there was higher net benefit when using the risk prediction model to classify in iduals as high risk compared with classifying all in iduals as high risk. The melanoma risk prediction model performs well and may be useful in prevention interventions reliant on a risk assessment using self-assessed risk factors.
Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2011
Abstract: To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome. Consecutive BRAF-tested Australian patients with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted. Forty-eight percent of patients had a BRAF mutation 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively P .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor. V600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis however, it may have impacted survival thereafter.
Common sequence variants on 20q11.22 confer melanoma susceptibility
Publisher: Springer Science and Business Media LLC
Date: 18-05-2008
DOI: 10.1038/NG.163
Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes
Publisher: Impact Journals, LLC
Date: 12-08-2015
Cell-type specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
Publisher: Cold Spring Harbor Laboratory
Date: 08-12-2017
DOI: 10.1101/231423
Abstract: Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type specific regulatory landscape of human melanocytes, which give rise to melanoma but account for % of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis -eQTL SNPs prior to LD-pruning and 4,997 eGenes (FDR .05), which are higher numbers than in any GTEx tissue type with a similar s le size. Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissues, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were not observed to be eGenes in two types of GTEx skin tissues or TCGA melanoma s les. The melanocyte dataset also identified cell-type specific trans- eQTLs with a pigmentation-associated SNP for four genes, likely through its cis -regulation of IRF4 , encoding a transcription factor implicated in human pigmentation phenotypes. Melanocyte eQTLs are enriched in cis -regulatory signatures found in melanocytes as well as melanoma-associated variants identified through genome-wide association studies (GWAS). Co-localization of melanoma GWAS variants and eQTLs from melanocyte and skin eQTL datasets identified candidate melanoma susceptibility genes for six known GWAS loci including unique genes identified by the melanocyte dataset. Further, a transcriptome-wide association study using published melanoma GWAS data uncovered four new loci, where imputed expression levels of five genes ( ZFP90, HEBP1, MSC, CBWD1 , and RP11-383H13.1 ) were associated with melanoma at genome-wide significant P -values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings and present a robust database for genomic research of melanoma risk and melanocyte biology.
Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types
Publisher: Elsevier BV
Date: 04-2018
GermlineCDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma
Publisher: BMJ
Date: 07-06-2017
DOI: 10.1136/JMEDGENET-2016-104402
Abstract: Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood both environmental and genetic risk factors could contribute to their aetiology. We performed whole-exome sequencing (WES) in a familial aggregation of three in iduals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation in Germline mutations in
An extended antibody microarray for surface profiling metastatic melanoma
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.JIM.2010.03.017
Abstract: An antibody microarray was developed for profiling the surface proteome of melanoma cells, which may facilitate melanoma sub-classification and provide important prognostic information useful in predicting the clinical behavior of the melanoma (e.g., likely sites of metastatic spread), patient outcome and treatment response. Forty-eight antibodies were selected based on their correlation with melanoma development, progression and/or prognosis and printed on nitrocellulose slides. The immobilised antibodies capture live cells expressing corresponding antigens to produce a cell binding dot pattern representing the surface antigen profile (immunophenotype) of the melanoma. Surface antigen signatures were determined for a normal melanocyte and 6 melanoma cell lines and cell suspensions prepared from 10 surgically excised melanoma lymph node metastases. A procedure for obtaining separate surface antigen profiles for melanoma cells and leukocytes from clinical lymph node s les was also developed using anti-CD45 magnetic beads. The capture of live, bead-bound leukocytes on these antibody microarrays provides a significant enhancement of this microarray technology. The antibody microarray will be used to profile panels of surgically excised melanoma lymph node metastases (melanoma and leukocyte fractions) to determine whether the immunophenotypes correlate with clinicopathological characteristics, disease progression and clinical outcome.
Skin cancer screening behaviours among individuals with a strong family history of malignant melanoma
Publisher: Springer Science and Business Media LLC
Date: 26-10-2010
Loss of heterozygosity in malignant melanoma at loci on chromosomes 11 and 17 implicated in the pathogenesis of other cancers
Publisher: Wiley
Date: 07-1993
Abstract: Forty-six cases of sporadic melanoma have been investigated for loss of heterozygosity at 4 loci: D11S29 (11q23), YNZ22 (17p13.3), TP53 (17p13.1) and NM23 (17q22). Each of the loci is thought to be important in the pathogenesis of other tumours. Mutations were found infrequently at the YNZ22, NM23, and TP53 loci. At D11S29, however, the frequency of mutation in the melanoma s les was high (67%) and mutations at this locus were associated with younger age at presentation. This region of chromosome 11 is also commonly mutated in breast cancers and haematological malignancies. Genetic aberrations at D11S29 may therefore represent nonspecific mutations found in several malignancies or part of a pathway common to the malignant phenotype.
Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas
Publisher: Elsevier BV
Date: 04-2018
Correction to: Overlapping genetic architecture between Parkinson disease and melanoma (Acta Neuropathologica, (2020), 139, 2, (347-364), 10.1007/s00401-019-02110-z)
Publisher: Springer Science and Business Media LLC
Date: 14-03-2020
Irregular Sleep/Wake Patterns Are Associated With Reduced Quality of Life in Post-treatment Cancer Patients: A Study Across Three Cancer Cohorts
Publisher: Frontiers Media SA
Date: 22-09-2021
DOI: 10.3389/FNINS.2021.700923
Abstract: Background: Cancer patients often describe poor sleep quality and sleep disruption as contributors to poor quality of life (QoL). In a cross-sectional study of post-treatment breast, endometrial, and melanoma cancer patients, we used actigraphy to quantify sleep regularity using the sleep regularity index (SRI), and examined relationships with reported sleep symptoms and QoL. Methods: Participants were recruited post-primary treatment (35 diagnosed with breast cancer, 24 endometrial cancer, and 29 melanoma) and wore an actigraphy device for up to 2 weeks and SRI was calculated. Self-report questionnaires for cancer-related QoL [European Organization for Research and Treatment of Cancer EORTC (QLQ-C30)] were completed. Data were compared using analysis of variance (ANOVA) or Chi-Square tests. Multivariate linear regression analysis was used to determine independent variable predictors for questionnaire-derived data. Results: Age distribution was similar between cohorts. Endometrial and breast cancer cohorts were predominantly female, as expected, and body mass index (BMI) was higher in the endometrial cancer cohort, followed by breast and melanoma. There were no differences between tumor groups in: total sleep time, sleep onset latency, bedtime, and SRI (breast 80.9 ± 8.0, endometrial 80.3 ± 12.2, and melanoma 81.4 ± 7.0) (all p & 0.05). A higher SRI was associated with both better functional and symptom scores, including increased global QoL, better physical functioning, less sleepiness and fatigue, better sleep quality, and associated with less nausea/vomiting, dyspnea, and diarrhea (all p & 0.05). Conclusion: In cancer patients post-treatment, greater sleep regularity is associated with increased global QoL, as well as better physical functioning and fewer cancer related symptoms. Improving sleep regularity may improve QoL for cancer patients.
An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics
Publisher: Elsevier BV
Date: 04-2018
Functional impairment of p16INK4A due to CDKN2A p.Gly23Asp missense mutation
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.MRFMMM.2009.08.007
Abstract: The CDKN2A locus encodes for two distinct tumor suppressor proteins, p16(INK4A) and p14(ARF), involved in cell cycle regulation. CDKN2A germline mutations have been associated with familial predisposition to melanoma and other tumor types. Besides bona-fide pathogenic mutations, many sequence variants have been identified, but their effect is not well known. We detected the p.Gly23Asp missense mutation in one of the two tested melanoma patients of a family with three melanoma cases. Even though the mutated amino acid is located in a conserved domain that specifically binds to and blocks the function of CDK4/6, its lack of segregation with disease suggested a series of functional assays to discriminate between a pathogenic variant and a neutral polymorphism. The effect of this mutation has been investigated exploiting four p16(INK4A) properties: its ability (i) to bind CDK4, (ii) to inhibit pRb phosphorylation, (iii) to evenly localize in the cell, and (iv) to cause cell cycle arrest. The mutant protein properties were evaluated transfecting three different cell lines (U2-OS and NM-39, both p16-null, and SaOS 2, p53 and pRb-null) with plasmids expressing either p16(wt), p16(23Asp), or the p16(32Pro) pathogenic variant. We found that p16(23Asp) was less efficient than p16(wt) in CDK4 binding, in inhibiting pRb phosphorylation, in inducing G1 cell cycle arrest moreover, its pattern of distribution throughout the cell was suggestive of protein aggregation, thus assessing a pathogenic role for p16(23Asp) in familial melanoma.
A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily
Publisher: Elsevier BV
Date: 10-2018
The nature and structure of psychological distress in people at high risk for melanoma: a factor analytic study
Publisher: Wiley
Date: 24-05-2011
DOI: 10.1002/PON.1976
Abstract: This study examined the psychometric properties of two commonly used measures of psychological distress, the Hospital Anxiety and Depression Scale (HADS) and the Impact of Events Scale (IES) in a s le of in iduals at high risk of developing melanoma due to strong family history. One hundred thirty-two in iduals with a known family-specific CDKN2A mutation (74% response rate) completed a mailed, self-administered questionnaire including the HADS and the IES. Initial correlational analyses were followed by both exploratory and confirmatory factor analyses, according to a predetermined procedure for order of analyses. Exploratory factor analyses found that neither a two-, three- or four-factor solution satisfactorily accounted for all IES items in the present s le. By contrast, a unidimensional account of the data emerged to best account for all IES items, leaving no items unaccounted for. In contrast, the traditional two-factor (anxiety and depression) structure of the HADS appeared to fit the data well. The traditional, two-factor (intrusion and avoidance) structure of the IES was not borne out within this familial melanoma cohort. Assessment of a single dimension of emotional distress in response to melanoma risk may facilitate more meaningful explorations of psychological adjustment in this context. These findings also raise questions about whether a post-traumatic stress framework is indeed the most appropriate framework to capture the unique nature of melanoma- or cancer-related distress.
RAB27A promotes melanoma cell invasion and metastasis via regulation of pro‐invasive exosomes
Publisher: Wiley
Date: 03-01-2019
DOI: 10.1002/IJC.32064
Abstract: Despite recent advances in targeted and immune-based therapies, advanced stage melanoma remains a clinical challenge with a poor prognosis. Understanding the genes and cellular processes that drive progression and metastasis is critical for identifying new therapeutic strategies. Here, we found that the GTPase RAB27A was overexpressed in a subset of melanomas, which correlated with poor patient survival. Loss of RAB27A expression in melanoma cell lines inhibited 3D spheroid invasion and cell motility in vitro, and spontaneous metastasis in vivo. The reduced invasion phenotype was rescued by RAB27A-replete exosomes, but not RAB27A-knockdown exosomes, indicating that RAB27A is responsible for the generation of pro-invasive exosomes. Furthermore, while RAB27A loss did not alter the number of exosomes secreted, it did change exosome size and altered the composition and abundance of exosomal proteins, some of which are known to regulate cancer cell movement. Our data suggest that RAB27A promotes the biogenesis of a distinct pro-invasive exosome population. These findings support RAB27A as a key cancer regulator, as well as a potential prognostic marker and therapeutic target in melanoma.
Impaired inhibition of NF-κB activity by melanoma-associated p16INK4a mutations
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.BBRC.2005.05.032
Abstract: The cyclin-dependent kinase inhibitor p16INK4a has been identified as tumor suppressor and melanoma predisposition gene. While its cell cycle inhibitory ability is important in protecting cells from uncontrolled growth and possible tumor formation, other functions of p16INK4a are likely to contribute to its nature as a tumor suppressor. p16INK4a binding and inhibition of the transcription factor NF-kappaB has been shown and is consistent with the reports of abnormally increased NF-kappaB activity in various cancers including melanoma. Here, we present evidence that wild type p16INK4a binds to the NF-kappaB subunit RelA more efficiently than melanoma-associated p16INK4a mutations. Furthermore, whereas wild type p16INK4a strongly inhibits NF-kappaB transcriptional activity, a subset of melanoma-associated p16INK4a mutants show reduced NF-kappaB inhibitory function. p16INK4a does not affect NF-kappaB nuclear translocation or DNA binding, suggesting a mechanism that reduces NF-kappaB transactivation activity.
Identifying challenges to implementation of clinical practice guidelines for sentinel lymph node biopsy in patients with melanoma in Australia: protocol paper for a mixed methods study.
Publisher: BMJ
Date: 02-2020
DOI: 10.1136/BMJOPEN-2019-032636
Abstract: Sentinel lymph node biopsy (SLNB) is a diagnostic procedure developed in the 1990s. It is currently used to stage patients with primary cutaneous melanoma, provide prognostic information and guide management. The Australian Clinical Practice Guidelines state that SLNB should be considered for patients with cutaneous melanoma mm in thickness (or .8 mm with high-risk pathology features). Until recently, sentinel lymph node (SLN) status was used to identify patients who might benefit from a completion lymph node dissection, a procedure that is no longer routinely recommended. SLN status is now also being used to identify patients who might benefit from systemic adjuvant therapies such as anti-programmed cell death 1 (PD1) checkpoint inhibitor immunotherapy or BRAF-directed molecular targeted therapy, treatments that have significantly improved relapse-free survival for patients with resected stage III melanoma and improved overall survival of patients with unresectable stage III and stage IV melanoma. Australian and international data indicate that approximately half of eligible patients receive an SLNB. This mixed-methods study seeks to understand the structural, contextual and cultural factors affecting implementation of the SLNB guidelines. Data collection will include: (1) cross-sectional questionnaires and semistructured interviews with general practitioners and dermatologists (2) semistructured interviews with other healthcare professionals involved in the diagnosis and early definitive care of melanoma patients and key stakeholders including researchers, representatives of professional colleges, training organisations and consumer melanoma groups and (3) documentary analysis of documents from government, health services and non-government organisations. Descriptive analyses and multivariable regression models will be used to examine factors related to SLNB practices and attitudes. Qualitative data will be analysed using thematic analysis. Ethics approval has been granted by the University of Sydney. Results will be disseminated through publications and presentations to clinicians, patients, policymakers and researchers and will inform the development of strategies for implementing SLNB guidelines in Australia.
The Role of Personalised Choice in Decision Support: A Randomized Controlled Trial of an Online Decision Aid for Prostate Cancer Screening
Publisher: Public Library of Science (PLoS)
Date: 06-04-2016
Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers
Publisher: Elsevier BV
Date: 04-2018
The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma
Publisher: Elsevier BV
Date: 04-2018
Improved Risk Prediction Calculator for Sentinel Node Positivity in Patients With Melanoma: The Melanoma Institute Australia Nomogram.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-08-2020
DOI: 10.1200/JCO.19.02362
Abstract: For patients with primary cutaneous melanoma, the risk of sentinel node (SN) metastasis varies according to several clinicopathologic parameters. Patient selection for SN biopsy can be assisted by National Comprehensive Cancer Network (NCCN) and ASCO/Society of Surgical Oncology (SSO) guidelines and the Memorial Sloan Kettering Cancer Center (MSKCC) online nomogram. We sought to develop an improved online risk calculator using alternative clinicopathologic parameters to more accurately predict SN positivity. Data from 3,477 patients with melanoma who underwent SN biopsy at Melanoma Institute Australia (MIA) were analyzed. A new nomogram was developed by replacing body site and Clark level from the MSKCC model with mitotic rate, melanoma subtype, and lymphovascular invasion. The predictive performance of the new nomogram was externally validated using data from The University of Texas MD Anderson Cancer Center (n = 3,496). The MSKCC model receiver operating characteristic curve had a predictive accuracy of 67.7% (95% CI, 65.3% to 70.0%). The MIA model had a predictive accuracy of 73.9% (95% CI, 71.9% to 75.9%), a 9.2% increase in accuracy over the MSKCC model ( P .001). Among the 2,748 SN-negative patients, SN biopsy would not have been offered to 22.1%, 13.4%, and 12.4% based on the MIA model, the MSKCC model, and NCCN or ASCO/SSO criteria, respectively. External validation generated a C-statistic of 75.0% (95% CI, 73.2% to 76.7%). A robust nomogram was developed that more accurately estimates the risk of SN positivity in patients with melanoma than currently available methods. The model only requires the input of 6 widely available clinicopathologic parameters. Importantly, the number of patients undergoing unnecessary SN biopsy would be significantly reduced compared with use of the MSKCC nomogram or the NCCN or ASCO/SSO guidelines, without losing sensitivity. An online calculator is available at www.melanomarisk.org.au .
A new modular and scalable detector for a time-of-flight PET scanner
Publisher: IEEE
Date: 10-2012
Unexpected UVR and non-UVR mutation burden in some acral and cutaneous melanomas
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1038/LABINVEST.2016.143
Abstract: Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Whole-genome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared. Three (of 35=8.6%) acral melanomas, all clinically and pathologically verified as arising from acral or subungual locations, had predominant UVR mutation burden, whereas four (of 140=2.9%) cutaneous melanomas showed predominant non-UVR mutations. Among the acral melanomas, the few that were UVR dominant occurred in younger patients, had a higher mutation load and a proportion of mutation burden due to UVR, which was similar to that in melanomas from intermittently UVR-exposed skin. Acral melanomas with a UVR signature occurred most frequently in subungual sites and included tumors harboring BRAF or NF1 mutations. Cutaneous melanomas dominated by non-UVR signatures had lower mutation burdens counts and their primary tumors were thicker and had more mitoses than in other cutaneous melanomas. No histopathological features predicted UVR dominance in acral melanomas or non-UVR dominance in cutaneous melanomas. Our finding of acral/subungual melanomas with predominant UVR mutagenesis suggests that the nail plate and acral skin do not provide complete protection from UVR. Our data also confirm that cutaneous melanomas not caused by UVR are infrequent. Identifying where mutation burden is discordant with primary tumor anatomical site is likely to be clinically significant when determining treatment options for metastatic acral and cutaneous melanoma patients.
Publisher Correction: Homologous recombination DNA repair defects in PALB2-associated breast cancers
Publisher: Springer Science and Business Media LLC
Date: 19-11-2019
DOI: 10.1038/S41523-019-0140-8
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Follow-Up Recommendations after Diagnosis of Primary Cutaneous Melanoma: A Population-Based Study in New South Wales, Australia
Publisher: Springer Science and Business Media LLC
Date: 03-01-2018
DOI: 10.1245/S10434-017-6319-Z
Abstract: Follow-up practices after diagnosis and treatment of primary cutaneous melanoma vary considerably. We aimed to determine factors associated with recommendations for follow-up setting, frequency, skin surveillance, and concordance with clinical guidelines. The population-based Melanoma Patterns of Care study documented clinicians' recommendations for follow-up for 2148 patients diagnosed with primary cutaneous melanoma over a 12-month period (2006/2007) in New South Wales, Australia. Multivariate log binomial regression models adjusted for patient and lesion characteristics were used to examine factors associated with follow-up practices. Of 2158 melanomas, Breslow thickness was 3 months were more likely to be recommended for females, less likely for people living in rural compared with urban areas, and less likely for thicker (≥ 1 mm) melanomas compared with in situ melanomas. Skin self-examination was encouraged in 84% of consultations and was less likely to be recommended for patients ≥ 70 years (PR 0.88, 95% CI 0.84-0.93) and for those with thicker (≥ 1 mm) melanomas (PR 0.92, 95% CI 0.86-0.99). Only 1% of patients were referred for psychological care. Follow-up recommendations were generally consistent with Australian national guidelines for management of melanoma, however some variations could be targeted to improve patient outcomes.
Melanoma risk for CDKN2A mutation carriers who are relatives of population-based case carriers in Australia and the UK
Publisher: BMJ
Date: 15-02-2011
A National Budget Impact Analysis of a Specialised Surveillance Programme for Individuals at Very High Risk of Melanoma in Australia
Publisher: Springer Science and Business Media LLC
Date: 05-01-2018
DOI: 10.1007/S40258-017-0368-0
Abstract: Specialised surveillance using total body photography and digital dermoscopy to monitor people at very high risk of developing a second or subsequent melanoma has been reported as cost effective. We aimed to estimate the 5-year healthcare budget impact of providing specialised surveillance for people at very high risk of subsequent melanoma from the perspective of the Australian healthcare system. A budget impact model was constructed to assess the costs of monitoring and potential savings compared with current routine care based on identification of patients at the time of a melanoma diagnosis. We used data from a published cost-effectiveness analysis of specialised surveillance, and Cancer Registry data, to estimate the patient population and healthcare costs for 2017-2021. When all eligible patients, estimated at 18% of patients with melanoma diagnosed annually in Australia, received specialised surveillance rather than routine care, the cumulative 5-year cost was estimated at $93.5 million Australian dollars ($AU) ($US 64 million) for specialised surveillance compared with $AU 120.7 million ($US 82.7 million) for routine care, delivering savings of $AU 27.2 million ($US 18.6 million). With a staggered introduction of 60% of eligible patients accessing surveillance in year 1, increasing to 90% in years 4 and 5, the cumulative cost over 5 years was estimated at $AU 98.1 million ($US 67.2 million), amounting to savings of $AU 22.6 million ($US 15.5 million) compared with routine care. Specialised melanoma surveillance is likely to provide substantial cost savings for the Australian healthcare system.
Benefits of a brief psychological intervention targeting fear of cancer recurrence in people at high risk of developing another melanoma: 12-month follow-up results of a randomized controlled trial
Publisher: Oxford University Press (OUP)
Date: 25-07-2020
DOI: 10.1111/BJD.17990
Abstract: People with melanoma want and need effective interventions for living with fear of cancer recurrence (FCR). This study reports the 12-month outcomes of a brief, psychological intervention designed to reduce FCR in people at high risk of developing another primary melanoma compared with usual care. In this two-arm randomized controlled trial, adults previously diagnosed with stage 0, I or II melanoma were randomly allocated to the intervention (n = 80) or control (usual care) arm (n = 84). The trial was registered with the Australian and New Zealand Clinical Trials Registry on 19 March 2013 (registration: ACTRN12613000304730). The intervention comprised a 76-page psychoeducational resource and three in idually tailored, telephone-based sessions with a psychologist, scheduled at specific time points around participants' dermatological appointments. The primary outcome was the level of self-reported fear of new or recurrent melanoma assessed at 12 months postintervention using the severity subscale of the Fear of Cancer Recurrence Inventory. Compared with the control arm, the intervention group reported significantly lower FCR at 12 months postintervention the between-group mean difference was -1·41 for FCR severity [95% confidence interval (CI) -2·6 to -0·2 P = 0·02] and -1·32 for FCR triggers (95% CI -2·6 to -0·02 P = 0·04). The odds ratio for FCR severity scores ≥13 (54% intervention, 63% control) was 0·59 (95% CI 0·30-1·14, P = 0·12). There were no differences between groups in secondary outcomes, such as anxiety, depression or health-related quality of life. The previously reported 6-month benefits of this brief, patient-centred psychological intervention in reducing FCR were found to continue 12 months postintervention, with no known adverse effects, supporting implementation as part of routine melanoma care.
Knowledge and attitudes of Australian dermatologists towards sentinel lymph node biopsy for melanoma: a mixed methods study
Publisher: Wiley
Date: 05-12-2020
DOI: 10.1111/AJD.13518
Abstract: In melanoma management, sentinel lymph node biopsy (SLNB) is used to stage patients and to indicate prognosis. More recently, it has been used to select patients for adjuvant therapy. This study aimed to report knowledge of and attitudes towards SLNB for patients with melanoma among Australian dermatologists. Mixed methods study using cross‐sectional questionnaires ( n = 88) and semi‐structured interviews ( n = 13), May–September 2019. Of the dermatologists surveyed, 56% thought SLNB had an important role in melanoma management, 26% were unsure and 18% thought SLNB unimportant. Of the 92% who would discuss SLNB with their patients, the main stated value of SLNB was for assessing eligibility for adjuvant therapies (79%) only 60% indicated SLNB was of value for providing prognostic information, and just over half (53%) thought it could improve staging. Interview data indicated that attitudes towards SLNB are shifting among dermatologists, driven by data from landmark clinical trials and the influence of professional networks. Accordingly, interviewees adopted one of three positions in relation to SLNB: (a) believed in utility of SLNB and adhered to the guidelines (b) were unconvinced about utility of SLNB but adhered to the guidelines and (c) were unconvinced about utility of SLNB and did not adhere to the guidelines. Although most of the dermatologists surveyed were familiar with and follow the SLNB recommendations, some disagreement with and distrust of the recommendations was evident. Greater acceptance of the SLNB recommendations appeared to be driven by the improved outcomes demonstrated in stage III patients receiving adjuvant systemic therapy.
Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways
Publisher: Springer Science and Business Media LLC
Date: 14-11-2018
DOI: 10.1038/S41467-018-06649-5
Abstract: The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 in iduals. We confirm known loci including MTAP , PLA2G6 , and IRF4 , and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1 , PPARGC1B , HDAC4 , FAM208B, DOCK8 , and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk ( KITLG an exception), while many melanoma risk loci do not alter nevus count. For ex le, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.
Cost-Effectiveness of Skin Surveillance Through a Specialized Clinic for Patients at High Risk of Melanoma
Publisher: American Society of Clinical Oncology (ASCO)
Date: 2017
Abstract: Clinical guidelines recommend that people at high risk of melanoma receive regular surveillance to improve survival through early detection. A specialized High Risk Clinic in Sydney, Australia was found to be effective for this purpose however, wider implementation of this clinical service requires evidence of cost-effectiveness and data addressing potential overtreatment of suspicious skin lesions. A decision-analytic model was built to compare the costs and benefits of specialized surveillance compared with standard care over a 10-year period, from a health system perspective. A high-risk standard care cohort was obtained using linked population data, comprising the Sax Institute’s 45 and Up cohort study, linked to Medicare Benefits Schedule claims data, the cancer registry, and hospital admissions data. Benefits were measured in quality-adjusted life-years gained. Sensitivity analyses were undertaken for all model parameters. Specialized surveillance through the High Risk Clinic was both less expensive and more effective than standard care. The mean saving was A$6,828 (95% CI, $5,564 to $8,092) per patient, and the mean quality-adjusted life-year gain was 0.31 (95% CI, 0.27 to 0.35). The main drivers of the differences were detection of melanoma at an earlier stage resulting in less extensive treatment and a lower annual mean excision rate for suspicious lesions in specialized surveillance (0.81 95% CI, 0.72 to 0.91) compared with standard care (2.55 95% CI, 2.34 to 2.76). The results were robust when tested in sensitivity analyses. Specialized surveillance was a cost-effective strategy for the management of in iduals at high risk of melanoma. There were also fewer invasive procedures in specialized surveillance compared with standard care in the community.
Mutation analysis of five candidate genes in familial breast cancer
Publisher: Springer Science and Business Media LLC
Date: 23-12-2006
DOI: 10.1007/S10549-006-9461-Z
Abstract: Most of the known breast cancer susceptibility genes (BRCA1, BRCA2, CHEK2 and ATM) are involved in the damage response pathway. Other members of this pathway are therefore good candidates for additional breast cancer susceptibility genes. ATR, along with ATM, plays a central role in DNA damage recognition and Chk1 relays checkpoint signals from both ATR and ATM. PPP2R1B and PPP2R5B code for subunits of protein phosphatase 2A (PP2A), which regulates autophosphorylation of ATM. In addition, EIF2S6/Int-6, which was originally identified as a common integration site for the mouse mammary tumour virus in virally induced mouse mammary tumours, is a candidate breast cancer susceptibility gene because of its putative role in maintaining chromosome stability. To investigate the role of ATR, CHK1, PPP2R1B, PPP2R5B and EIF2S6/Int-6, we carried out mutation analysis of these genes in the index cases from non-BRCA1/BRCA2 breast cancer families. We also screened sporadic breast tumours for somatic mutations in PPP2R1B and PPP2R5B. Although we identified many novel variants, we found no evidence that highly penetrant germline mutations in these five genes contribute to familial breast cancer susceptibility.
Accuracy of self-reported nevus and pigmentation phenotype compared with clinical assessment in a population-based study of young Australian Adults
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2015
DOI: 10.1158/1055-9965.EPI-14-1203
Abstract: Background: Awareness of in idual risk may encourage improved prevention and early detection of melanoma. Methods: We evaluated the accuracy of self-reported pigmentation and nevus phenotype compared with clinical assessment, and examined agreement between nevus counts from selected anatomical regions. The s le included 456 cases with invasive cutaneous melanoma diagnosed between ages 18 to 39 years and 538 controls from the population-based Australian Melanoma Family Study. Participants completed a questionnaire about their pigmentation and nevus phenotype, and attended a dermatologic skin examination. Results: There was strong agreement between self-reported and clinical assessment of eye color [κ, = 0.78 95% confidence interval (CI), 0.74–0.81] and moderate agreement for hair color (κ = 0.46 95% CI, 0.42–0.50). Agreement between self-reported skin color and spectrophotometer-derived measurements was poor (κ = 0.12 95% CI, 0.08–0.16) to moderate (Spearman correlation rs = −0.37 95% CI, −0.32 to −0.42). Participants tended to underestimate their nevus counts and pigmentation men were more likely to underreport their skin color. The rs was 0.43 (95% CI, 0.38–0.49) comparing clinical total body nevus counts with self-reported nevus categories. There was good agreement between total body nevus counts and site-specific nevus counts, particularly on both arms. Conclusions: Young adults have suboptimal accuracy when assessing important risk characteristics including nevus numbers and pigmentation. Measuring nevus count on the arms is a good predictor of full body nevus count. Impact: These results have implications for the likely success of targeted public health programs that rely on self-assessment of these factors. Cancer Epidemiol Biomarkers Prev 24(4) 736–43. ©2015 AACR.
Supplementary Data from Distinct Molecular Profiles and Immunotherapy Treatment Outcomes of V600E and V600K <i>BRAF</i>-Mutant Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22467960
Abstract: Supplementary Tables 1-2, and Figures 1-5.
A model of prostate-specific antigen screening outcomes for low- to high-risk men: Information to support informed choices
Publisher: American Medical Association (AMA)
Date: 28-09-2009
DOI: 10.1001/ARCHINTERNMED.2009.282
Abstract: Information is needed to aid in idual decision making about prostate-specific antigen (PSA) screening. We aimed to provide such information for men aged 40, 50, 60, and 70 years at low, moderate, and high risk for prostate cancer. A Markov model compared patients with vs without annual PSA screening using a 20% relative risk (RR) reduction (RR = 0.8) in prostate cancer mortality as a best-case scenario. The model estimated numbers of biopsies, prostate cancers, and deaths from prostate cancer per 1000 men over 10 years and cumulated to age 85 years. Benefits and harms vary substantially with age and familial risk. Using 60-year-old men with low risk as an ex le, of 1000 men screened annually, we estimate that 115 men will undergo biopsy triggered by an abnormal PSA screen result and that 53 men will be diagnosed as having prostate cancer over 10 years compared with 23 men diagnosed as having prostate cancer among 1000 unscreened men. Among screened men, 3.5 will die of prostate cancer over 10 years compared with 4.4 deaths in unscreened men. For 1000 men screened from 40 to 69 years of age, there will be 27.9 prostate cancer deaths and 639.5 deaths overall by age 85 years compared with 29.9 prostate cancer deaths and 640.4 deaths overall in unscreened men. Higher-risk men have more prostate cancer deaths averted but also more prostate cancers diagnosed and related harms. Men should be informed of the likely benefits and harms of PSA screening. These estimates can be used to support in idual decision making.
Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling
Publisher: Springer Science and Business Media LLC
Date: 04-03-2021
DOI: 10.1038/S41467-021-21576-8
Abstract: Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by s ling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour s les reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.
Chemotherapy in metastatic melanoma: Phase II studies of amsacrine, mitoxantrone and bisantrene
Publisher: Elsevier BV
Date: 1986
DOI: 10.1016/0277-5379(86)90347-0
Abstract: In a phase II study 20 patients with measurable metastatic melanoma were treated with amsacrine 120 mg/m2 every 3 weeks. No objective responses were observed. In a separate study 29 patients received mitoxantrone 12-14 mg/m2 every 3-4 weeks. One objective partial response was seen. The drug was well tolerated. Seventeen patients were treated with bisantrene 135-200 mg/m2 weekly. No objective responses were observed. Phlebitis was the major non-hematologic toxicity of bisantrene. These agents are not recommended for treatment of malignant melanoma.
Data Independent Acquisition Proteomic Analysis Can Discriminate between Actinic Keratosis, Bowen’s Disease, and Cutaneous Squamous Cell Carcinoma
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.JID.2019.06.128
Abstract: Actinic keratosis, Bowen's disease and cutaneous squamous cell carcinoma (cSCC) are heterogeneous keratinocytic skin lesions. Biomarkers that can accurately stratify these lesion types are needed to support a new paradigm of personalized and precise management of skin neoplasia. In this paper, we used a data independent acquisition proteomics workflow, sequential window acquisition of all theoretical mass spectra, to analyze formalin-fixed paraffin-embedded s les of normal skin and keratinocytic skin lesions, including well-differentiated, moderately differentiated and poorly differentiated cSCC lesions. We quantified 3,574 proteins across the 93 s les studied. Differential abundance analysis identified 19, 5, and 6 protein markers exclusive to actinic keratosis, Bowen's disease and cSCC lesions, respectively. Among cSCC lesions of various levels of tumor differentiation, 118, 230, and 17 proteins showed a potential as biomarkers of well-differentiated, moderately differentiated and poorly differentiated cSCC lesions, respectively. Bioinformatics analysis revealed that actinic keratosis and cSCC lesions were associated with decreased apoptosis, and Bowen's disease lesions with over-representation of the DNA damage repair pathway. Differential expression of alternatively spliced FGFR2, Rho guanosine triphosphatase signaling, and RNA metabolism proteins were associated with the level of cSCC tumor differentiation. Proteome profiles also separated keratinocytic skin lesion subtypes on principal components analysis. Overall, protein markers have excellent potential to discriminate keratinocytic skin lesion subtypes and facilitate new diagnostic and therapeutic strategies.
A multi-step classifier addressing cohort heterogeneity improves performance of prognostic biomarkers in three cancer types
Publisher: Impact Journals, LLC
Date: 11-08-2016
Genetic testing for melanoma risk: a prospective cohort study of uptake and outcomes among Australian families.
Publisher: Elsevier BV
Date: 04-2009
Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways
Publisher: Cold Spring Harbor Laboratory
Date: 07-08-2017
DOI: 10.1101/173112
Abstract: The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped in iduals. We confirm known loci including MTAP , PLA2G6 , and IRF4 , and detect novel SNPs at a genome-wide level of significance in KITLG , DOCK8 , and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A , CYP1B1 , PPARGC1B , HDAC4 , FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1 , reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk ( KITLG an exception), while many melanoma risk loci do not alter nevus count. For ex le, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.
Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context
Publisher: Elsevier BV
Date: 04-2018
Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas
Publisher: Elsevier BV
Date: 04-2018
Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility
Publisher: Springer Science and Business Media LLC
Date: 27-04-2020
Loss-of-Function Fibroblast Growth Factor Receptor-2 Mutations in Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 2009
DOI: 10.1158/1541-7786.MCR-08-0021
Abstract: We report that 10% of melanoma tumors and cell lines harbor mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. These novel mutations include three truncating mutations and 20 missense mutations occurring at evolutionary conserved residues in FGFR2 as well as among all four FGFRs. The mutation spectrum is characteristic of those induced by UV radiation. Mapping of these mutations onto the known crystal structures of FGFR2 followed by in vitro and in vivo studies show that these mutations result in receptor loss of function through several distinct mechanisms, including loss of ligand binding affinity, impaired receptor dimerization, destabilization of the extracellular domains, and reduced kinase activity. To our knowledge, this is the first demonstration of loss-of-function mutations in a class IV receptor tyrosine kinase in cancer. Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer. (Mol Cancer Res 2009 (1):41–54)
Neurotropic melanoma: An analysis of the clinicopathological features, management strategies and survival outcomes for 671 patients treated at a tertiary referral center
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1038/MODPATHOL.2017.76
Abstract: Neurotropic cutaneous melanoma is a rare melanoma subtype that invades nerves and is often associated with desmoplastic melanoma. Limited data suggest that it has a greater propensity to recur locally, but it is unknown whether its behavior differs from that of other melanoma subtypes, including desmoplastic melanoma. We investigated clinicopathological predictors of outcome in a cohort of 671 patients with neurotropic melanoma to develop evidence-based management recommendations. Patients with primary neurotropic melanoma diagnosed from 1985 to 2013 were identified from the Melanoma Institute Australia database, along with a control cohort of 718 non-neurotropic melanoma patients. Features predictive of sentinel lymph node status, recurrence, melanoma-specific survival and response to adjuvant radiotherapy were sought. Neither local recurrence (hazard ratio: 1.28 (0.73-2.25) P=0.39) nor melanoma-specific survival (hazard ratio: 0.79 (0.55-1.15) P=0.22) were significantly affected by the presence of neurotropism on multivariate analysis. However, there was a markedly reduced likelihood of sentinel node positivity (hazard ratio: 0.61 (0.41-0.89) P=0.01) in neurotropic melanoma patients. Surgical margins ≥8mm halved the recurrence risk compared with <2 mm margins (hazard ratio: 0.46 (0.31-0.68) P<0.001). Additionally, in neurotropic melanoma patients with <8 mm margins, adjuvant radiotherapy halved the recurrence risk (hazard ratio: 0.48 (0.27-0.87) P=0.02). This, the largest study of neurotropic melanoma reported to date, has demonstrated that the presence of neurotropism does not alter the risk of melanoma recurrence or survival but does reduce the likelihood of sentinel node positivity. For successful treatment of neurotropic melanoma, adequate excision margins are of paramount importance. However, when adequate margins cannot be achieved, adjuvant radiotherapy reduces the risk of recurrence.
Anatomic position determines oncogenic specificity in melanoma
Publisher: Cold Spring Harbor Laboratory
Date: 15-11-2020
DOI: 10.1101/2020.11.14.383083
Abstract: Oncogenic alterations to DNA are not transforming in all cellular contexts 1, 2 . This may be due to pre-existing transcriptional programs in the cell of origin. Here, we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet, or under the nails 3 . We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma but CRKL lifications in acral melanoma. We modeled these changes in transgenic zebrafish models and found that CRKL-driven tumors predominantly formed in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin/limb melanocytes, compared to body melanocytes, revealed a positional identity gene program typified by posterior HOX13 genes. This positional gene program synergized with CRKL to drive tumors at acral sites. Abrogation of this CRKL-driven program eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.
Sex differences in oncogenic mutational processes
Publisher: Springer Science and Business Media LLC
Date: 28-08-2020
DOI: 10.1038/S41467-020-17359-2
Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.
Issues Faced by Unaffected Men With a Family History of Prostate Cancer: A Multidisciplinary Overview
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2008
DOI: 10.1016/J.JURO.2008.03.020
Abstract: Despite the established importance of the role of family history in prostate cancer, relatively little research encompasses the psychosocial issues relevant to unaffected men with a family history of prostate cancer. To determine the completeness and quality of available literature on the issues faced by men with a high risk of prostate cancer, we conducted a multidisciplinary review of the literature to provide some guidance on the information that clinicians might provide to men who are concerned about family history. A structured literature search was conducted by a multidisciplinary team of clinicians and researchers who reviewed the medical and psychosocial literature, and identified 21 relevant studies. Research suggests that many high risk patients are concerned about the risk of prostate cancer, and some may significantly overestimate that risk. Several studies have shown high screening rates among high risk patients and high levels of interest in genetic testing for prostate cancer risk should it become available, yet many men also report a desire for more information about their personal risk and risk management options. Given the lack of clear data on the efficacy of prostate cancer screening among high risk patients, clinicians could consider providing men who are concerned about family history with information on their personal risk, help them to clarify the potential benefits, limitations and harms of prostate cancer screening in their situation, and then support their choice regarding the management of prostate cancer risk.
Risk of developing a second primary melanoma after a first primary melanoma in a population-based Australian cohort
Publisher: Oxford University Press (OUP)
Date: 22-03-2023
DOI: 10.1093/BJD/LJAD076
Abstract: This cross-sectional survey identified risk factors for developing a second primary melanoma. Patients with melanoma who had characteristics such as male sex, older age, high naevus count, or melanoma on the trunk or upper limbs had a substantially higher risk of subsequent melanoma and should therefore be more intensively monitored.
Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer
Publisher: Springer Science and Business Media LLC
Date: 21-10-2005
DOI: 10.1186/BCR1336
Proteomics: An emerging approach for the diagnosis and classification of cutaneous squamous cell carcinoma and its precursors
Publisher: Elsevier BV
Date: 07-2020
Cell death and barrier disruption by clinically used iodine concentrations
Publisher: Life Science Alliance, LLC
Date: 21-03-2023
Abstract: Povidone-iodine (PVP-I) inactivates a broad range of pathogens. Despite its widespread use over decades, the safety of PVP-I remains controversial. Its extended use in the current SARS-CoV-2 virus pandemic urges the need to clarify safety features of PVP-I on a cellular level. Our investigation in epithelial, mesothelial, endothelial, and innate immune cells revealed that the toxicity of PVP-I is caused by diatomic iodine (I 2 ), which is rapidly released from PVP-I to fuel organic halogenation with fast first-order kinetics. Eukaryotic toxicity manifests at below clinically used concentrations with a threshold of 0.1% PVP-I (wt/vol), equalling 1 mM of total available I 2 . Above this threshold, membrane disruption, loss of mitochondrial membrane potential, and abolition of oxidative phosphorylation induce a rapid form of cell death we propose to term iodoptosis. Furthermore, PVP-I attacks lipid rafts, leading to the failure of tight junctions and thereby compromising the barrier functions of surface-lining cells. Thus, the therapeutic window of PVP-I is considerably narrower than commonly believed. Our findings urge the reappraisal of PVP-I in clinical practice to avert unwarranted toxicity whilst safeguarding its benefits.
10q deletions in metastatic cutaneous melanoma
Publisher: Elsevier BV
Date: 1998
DOI: 10.1016/S0165-4608(97)00016-2
Abstract: Cytogenetic and allelic deletion studies have indicated that the loss of distal chromosome 10q may be a frequent and early event in melanoma tumorigenesis. We have studied nine polymorphic markers spanning 56 cM of this region in 27 advanced melanomas and find that half exhibited loss of the entire region, but none had more limited deletions. Because all these tumors had a codeletion of 9p, the 10q deletion event is likely to impair a pathway other than the cyclin-dependent kinase-mediated phosphorylation of the retinoblastoma protein.
Diagnosis and clinical management of melanoma patients at higher risk of a new primary melanoma: A population-based study in New South Wales, Australia
Publisher: Wiley
Date: 08-2017
DOI: 10.1111/AJD.12530
Abstract: To describe the method of diagnosis, clinical management and adherence to clinical practice guidelines for melanoma patients at high risk of a subsequent primary melanoma, and compare this with melanoma patients at lower risk. The Melanoma Patterns of Care study was a population-based, observational study based on doctors' reported clinical management of melanoma patients in New South Wales, Australia, diagnosed with in situ or invasive melanoma over a 12-month period from October 2006. Of 2605 patients with localised melanoma, 1019 (39%) were defined as at higher risk due to the presence of one or more of the following factors: a family history of melanoma (11%), multiple primary melanomas (17%), or many naevi (24%). Compared to patients at lower risk, high risk patients were more likely to receive their initial care from a primary care physician (56% vs 50%, P = 0.002), have their melanoma detected during a routine skin check (40% vs 33%, P < 0.001), have their lesion assessed with dermoscopy (63% vs 56%, P = 0.002), and be encouraged to have skin surveillance (84% vs 77%, P < 0.001) and skin self-examination (87% vs 83%, P = 0.03). Higher socioeconomic status and urban residence were associated with patients at higher risk receiving initial treatment from a specialist doctor. Clinical management of higher risk patients was more likely to conform to clinical practice guidelines for diagnosis and skin surveillance than to melanoma patients at lower risk.
Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility.
Publisher: Wiley
Date: 21-11-2018
DOI: 10.1002/IJC.31791
Abstract: Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15-30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantly affecting those over 65 years of age. We performed genomic analysis of 50 AYA melanoma patients (onset 10-30 years, median 20) 25 underwent whole genome sequencing (WGS) of both tumor and germline DNA, exome data were retrieved from 12 TCGA AYA cases, and targeted DNA sequencing was conducted on 13 cases. The AYA cases were compared with WGS data from 121 adult cutaneous melanomas. Similar to mature adult cutaneous melanomas, AYA melanomas showed a high mutation burden and mutation signatures of ultraviolet radiation (UVR) damage. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the AYA WGS cohort were double the rates observed in adult melanomas (Q < 6.0 × 10
Data from Distinct Molecular Profiles and Immunotherapy Treatment Outcomes of V600E and V600K <i>BRAF</i>-Mutant Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6526800.V1
Abstract: AbstractPurpose: i BRAF /i V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to i BRAFi /i ± i MEKi /i . We investigated mechanisms for this and explored whether genotype affects response to immunotherapy. Experimental Design: Pretreatment formalin-fixed paraffin-embedded tumors from patients treated with i BRAFi /i ± i MEKi /i underwent gene expression profiling and DNA sequencing. Molecular results were validated using The Cancer Genome Atlas (TCGA) data. An independent cohort of V600E/K patients treated with anti–PD-1 immunotherapy was examined. Results: Baseline tissue and clinical outcome with i BRAFi /i ± i MEKi /i were studied in 93 patients (78 V600E, 15 V600K). V600K patients had numerically less tumor regression (median, −31% vs. −52%, i P /i = 0.154) and shorter progression-free survival (PFS median, 5.7 vs. 7.1 months, i P /i = 0.15) compared with V600E. V600K melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6, confirmed with TCGA data (116 V600E, 17 V600K). Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E. Higher mutational load was observed in V600K, with a higher proportion of mutations in i PIK3R1 /i and tumor-suppressor genes. In patients treated with anti–PD-1, V600K ( i n /i = 19) had superior outcomes than V600E ( i n /i = 84), including response rate (53% vs. 29%, i P /i = 0.059), PFS (median, 19 vs. 2.7 months, i P /i = 0.049), and overall survival (20.4 vs. 11.7 months, i P /i = 0.081). Conclusions: i BRAF /i V600K melanomas appear to benefit less from i BRAFi /i ± i MEKi /i than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy. /
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541620.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Is there a role for genetic testing in patients with melanoma?
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2003
DOI: 10.1097/00001622-200303000-00007
Abstract: Autosomal dominant inheritance of mutations in the locus or the gene may confer a high risk of cutaneous melanoma development. The penetrance of mutations is influenced by UV exposure. Inherited variants in the melanocortin-1 receptor also confer increased risk of cutaneous melanoma. Features associated with increased genetic susceptibility to cutaneous melanoma include the presence of multiple affected first-degree relatives on one side of the family, multiple primary melanomas in the same in idual, earlier age of onset, and the presence of multiple atypical nevi, but none of these factors reliably predicts for the presence of mutations. It is currently premature to offer predictive DNA testing for melanoma outside of defined research protocols. This is because of (1). the low likelihood of finding mutations in known melanoma susceptibility genes, even in more than 60% of melanoma-prone kindreds (2). the broad confidence limits on current estimates of lifetime penetrance of mutations and the wide variation in this penetrance with locality (3). a high "background" incidence of melanoma in non-mutation carriers in melanoma-prone families (4). current uncertainties about the factors determining the functionality and phenotypic expression of the trait among carriers of these mutations (penetrance), even if found and (5). the lack of proved efficacy of melanoma prevention and surveillance strategies, even for mutation carriers. Rather than singling out those deemed to be at high risk because of family history, all patients carrying risk factors for cutaneous melanoma should be subject to stringent programs of sun protection and skin surveillance.
Genomic Classification of Cutaneous Melanoma
Publisher: Elsevier BV
Date: 06-2015
UV-associated mutations underlie the etiology of MCV-negative Merkel cell carcinomas
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2015
DOI: 10.1158/0008-5472.CAN-15-1877
Abstract: Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or lified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell–infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. Cancer Res 75(24) 5228–34. ©2015 AACR.
Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples
Publisher: Springer Science and Business Media LLC
Date: 21-09-2020
DOI: 10.1038/S41467-020-18151-Y
Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA s les, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological ergences between two reproducible somatic variant detection efforts.
A 14-Protein Signature for Rapid Identification of Poor Prognosis Stage III Metastatic Melanoma
Publisher: Wiley
Date: 19-01-2018
Abstract: To validate differences in protein levels between good and poor prognosis American Joint Committee on Cancer (AJCC) stage III melanoma patients and compile a protein panel to stratify patient risk. Protein extracts from melanoma metastases within lymph nodes in patients with stage III disease with good (n = 16, >4 years survival) and poor survival (n = 14, <2 years survival) were analyzed by selected reaction monitoring (SRM). Diagonal Linear Discriminant Analysis (DLDA) was performed to generate a protein biomarker panel. SRM analysis identified ten proteins that were differentially abundant between good and poor prognosis stage III melanoma patients. The ten differential proteins were combined with 22 proteins identified in our previous work. A panel of 14 proteins was selected by DLDA that was able to accurately classify patients into prognostic groups based on levels of these proteins. The ten differential proteins identified by SRM have biological significance in cancer progression. The final signature of 14 proteins identified by SRM could be used to identify AJCC stage III melanoma patients likely to have poor outcomes who may benefit from adjuvant systemic therapy.
The Prognostic and Predictive Value of Melanoma-related MicroRNAs Using Tissue and Serum: A MicroRNA Expression Analysis
Publisher: Elsevier BV
Date: 07-2015
The melanoma-associated 24 base pair duplication in p16INK4a is functionally impaired
Publisher: Wiley
Date: 2005
DOI: 10.1002/IJC.21265
Abstract: Melanoma-associated germline mutations affecting the tumor suppressor and cyclin-dependent kinase (CDK) inhibitor, CDKN2A 16INK4a, have been identified in over 100 melanoma-prone families worldwide. To predict the melanoma risk for carriers of specific mutations, mutant p16INK4a can be tested in biochemical and cellular assays. In most cases, p16INK4a mutations with predicted disease relation, due to segregation with melanoma, are functionally impaired in such assays. The N-terminal 24 base pair duplication of CDKN2A, however, encodes a p16INK4a variant previously shown to have wild-type function, despite segregating with melanoma in at least 5 melanoma families. To clarify whether the duplication mutation has a cell cycle regulatory defect or behaves like wild-type p16INK4a, we reanalyzed the cell cycle-inhibitory activity of this mutation. Stable cell clones of the p16-null WMM1175 melanoma cell line inducible for ectopic p16INK4a were used in this study. In these cells, p16INK4a expression can be controlled at physiologic levels. Our results show that in comparison to wild-type p16INK4a, the duplication mutant induced weaker S-phase inhibition and cells expressing this mutant form of p16INK4a retained colony formation ability. We also show that the cell cycle-regulatory defect of the p16INK4a duplication mutant was associated with decreased inhibition of pRb phosphorylation even though it retained significant binding to CDK4.
Oncogenic Signaling Pathways in The Cancer Genome Atlas
Publisher: Elsevier BV
Date: 04-2018
Tumor Mutation Burden and Structural Chromosomal Aberrations Are Not Associated with T-cell Density or Patient Survival in Acral, Mucosal, and Cutaneous Melanomas.
Publisher: American Association for Cancer Research (AACR)
Date: 11-2020
DOI: 10.1158/2326-6066.CIR-19-0835
Abstract: Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous melanoma subtypes, which are known to have different TMB. It is also unknown whether chromosomal structural mutations [structural variant (SV) mutations] contribute to the immunogenicity in acral and mucosal melanomas where such aberrations are common. We stained 151 cutaneous and 35 acral and mucosal melanoma patient s les using quantitative IHC and correlated immune infiltrate phenotypes with TMB and other genomic profiles. TMB and SVs did not correlate with the densities of CD8+ lymphocytes, CD103+ tumor-resident T cells (Trm), CD45RO+ cells, and other innate and adaptive immune cell subsets in cutaneous and acral/mucosal melanoma tumors, respectively, including in analyses restricted to the site of disease and in a validation cohort. In 43 patients with stage III treatment-naïve cutaneous melanoma, we found that the density of immune cells, particularly Trm, was significantly associated with patient survival, but not with TMB. Overall, TMB and chromosomal structural aberrations are not associated with protective antitumor immunity in treatment-naïve melanoma.
Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics
Publisher: Elsevier BV
Date: 04-2018
Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549709
Abstract: Abstract Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation uveal melanoma occurs in the eyes mucosal melanoma occurs in internal mucous membranes and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes. Significance: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-12-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2711 /a /i /
Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation
Publisher: Elsevier BV
Date: 04-2018
Surface antigen profiles of leukocytes and melanoma cells in lymph node metastases are associated with survival in AJCC stage III melanoma patients
Publisher: Springer Science and Business Media LLC
Date: 17-01-2014
Association Between Melanoma Detected During Routine Skin Checks and Mortality
Publisher: American Medical Association (AMA)
Date: 12-2021
Data from Distinct Molecular Profiles and Immunotherapy Treatment Outcomes of V600E and V600K <i>BRAF</i>-Mutant Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6526800
Abstract: AbstractPurpose: i BRAF /i V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to i BRAFi /i ± i MEKi /i . We investigated mechanisms for this and explored whether genotype affects response to immunotherapy. Experimental Design: Pretreatment formalin-fixed paraffin-embedded tumors from patients treated with i BRAFi /i ± i MEKi /i underwent gene expression profiling and DNA sequencing. Molecular results were validated using The Cancer Genome Atlas (TCGA) data. An independent cohort of V600E/K patients treated with anti–PD-1 immunotherapy was examined. Results: Baseline tissue and clinical outcome with i BRAFi /i ± i MEKi /i were studied in 93 patients (78 V600E, 15 V600K). V600K patients had numerically less tumor regression (median, −31% vs. −52%, i P /i = 0.154) and shorter progression-free survival (PFS median, 5.7 vs. 7.1 months, i P /i = 0.15) compared with V600E. V600K melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6, confirmed with TCGA data (116 V600E, 17 V600K). Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E. Higher mutational load was observed in V600K, with a higher proportion of mutations in i PIK3R1 /i and tumor-suppressor genes. In patients treated with anti–PD-1, V600K ( i n /i = 19) had superior outcomes than V600E ( i n /i = 84), including response rate (53% vs. 29%, i P /i = 0.059), PFS (median, 19 vs. 2.7 months, i P /i = 0.049), and overall survival (20.4 vs. 11.7 months, i P /i = 0.081). Conclusions: i BRAF /i V600K melanomas appear to benefit less from i BRAFi /i ± i MEKi /i than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy. /
Multiplex melanoma families are enriched for polygenic risk
Publisher: Oxford University Press (OUP)
Date: 27-07-2020
DOI: 10.1093/HMG/DDAA156
Abstract: Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of in idually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10−5 and 6.3 × 10−45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.
Predictors of psychological distress among individuals with a strong family history of malignant melanoma
Publisher: Wiley
Date: 28-12-2007
DOI: 10.1111/J.1399-0004.2007.00949.X
Abstract: Despite rapid advancements in molecular genetics research, little is known about the psychological experiences of in iduals with a family history of melanoma. The present study aimed to identify factors contributing to psychological distress among affected and unaffected in iduals with a strong family history of melanoma. A total of 121 adults who had recently been informed of the identification of a family-specific mutation in the CDKN2A melanoma susceptibility gene, completed a self-report questionnaire assessing cancer-specific and generalized distress, and a variety of potential predictors. Having a personal history of melanoma (OR = 3.37, p = 0.033), perceiving greater family implications of melanoma (OR = 2.52, p < 0.0001), and the tendency to monitor for threatening information (OR = 3.12, p = 0.008) were associated with melanoma-specific distress. Being childless (beta = 2.09, p = 0.007), perceiving sun exposure as an important cause of melanoma (beta = 1.15, p = 0.015), and perceiving greater family implications of melanoma (beta = 1.02, p = 0.002) were associated with greater generalized anxiety, while monitoring moderated the relationship between endorsement of a genetic model of melanoma and generalized anxiety (p = 0.005). As in other common familial cancers, distress was relatively uncommon in this familial melanoma cohort, even after notification of the presence of a family mutation. Participants do not contemplate their melanoma risk in isolation, but evaluate their risk vis-à-vis the experiences of their relatives.
Pathogenic Germline Variants in 10,389 Adult Cancers
Publisher: Elsevier BV
Date: 04-2018
Psycho‐educational interventions for melanoma survivors: a systematic review
Publisher: Wiley
Date: 30-08-2012
DOI: 10.1002/PON.3165
Abstract: To systematically review psycho-educational interventions developed for melanoma survivors. Electronic databases Medline, PsycINFO, Embase, and CINAHL were systematically searched using key words and subject headings for articles describing educational or psychological interventions designed specifically for people affected by melanoma. Twenty-seven articles, generated by 16 unique interventions, were included for detailed review. Overall, educational interventions showed increased patient satisfaction with clinical care and information provision, as well as increased frequency of skin self-examination, although accuracy and thoroughness of skin examination were seldom reported. Participation in psychological interventions was associated with decreases in anxiety, health-related distress, and melanoma recurrence rates, as well as positive changes in coping with illness. Programs, when implemented as part of routine clinical care, were found to be cost-effective. Interventions in this field vary widely, limiting the identification of 'active ingredients' for psychological or behavioral change. Future intervention studies should ensure sufficient information is provided to support program replication and comprehensive assessment of program outcomes.
SurvBenchmark: comprehensive benchmarking study of survival analysis methods using both omics data and clinical data
Publisher: Oxford University Press (OUP)
Date: 2022
DOI: 10.1093/GIGASCIENCE/GIAC071
Abstract: Survival analysis is a branch of statistics that deals with both the tracking of time and the survival status simultaneously as the dependent response. Current comparisons of survival model performance mostly center on clinical data with classic statistical survival models, with prediction accuracy often serving as the sole metric of model performance. Moreover, survival analysis approaches for censored omics data have not been thoroughly investigated. The common approach is to binarize the survival time and perform a classification analysis. Here, we develop a benchmarking design, SurvBenchmark, that evaluates a erse collection of survival models for both clinical and omics data sets. SurvBenchmark not only focuses on classical approaches such as the Cox model but also evaluates state-of-the-art machine learning survival models. All approaches were assessed using multiple performance metrics these include model predictability, stability, flexibility, and computational issues. Our systematic comparison design with 320 comparisons (20 methods over 16 data sets) shows that the performances of survival models vary in practice over real-world data sets and over the choice of the evaluation metric. In particular, we highlight that using multiple performance metrics is critical in providing a balanced assessment of various models. The results in our study will provide practical guidelines for translational scientists and clinicians, as well as define possible areas of investigation in both survival technique and benchmarking strategies.
Isolation and preliminary characterisation of an X-ray-sensitive mamamalian mutant cell line (WMXRS-1)
Publisher: Elsevier BV
Date: 05-1994
DOI: 10.1016/0921-8777(94)90070-1
Abstract: Mammalian cell lines that are sensitive to particular genotoxic agents have proved the most effective starting point for the cloning of human DNA-repair genes. After ethyl methanesulphonate mutagenesis of the parent murine fibroblast L-cell line, a new mammalian X-ray-sensitive cell line (WMXRS-1) was isolated. For selection of the mutant, a novel detection method was used: putative X-ray-sensitive clones were identified by their lack of incorporation of the DNA precursor, bromodeoxyuridine, after irradiation. The WMXRS-1 cell line was collaterally sensitive to ultraviolet radiation and some other agents known to be removed from DNA by the nucleotide excision repair pathway, but not to bleomycin or hydrogen peroxide. In relation to the wild-type strain, WMXRS-1 showed a similar pattern of induction of micronuclei up to an X-ray dose of 4 Gray and a similar DNA double-strand break (dsb) induction profile. The overall level of dsb rejoining was the same in the parent and mutant lines. However, WMXRS-1 demonstrated a reduced initial rate of dsb-rejoining, perhaps accounting for its radiosensitivity. WMXRS-1 also showed a greater G2 cell cycle phase accumulation after treatment with mitomycin-C. The cross-sensitivity profile and strand-break rejoining deficiency phenotype of WMXRS-1 is unique amongst previously characterised mammalian mutant cell lines.
Specialised skin cancer spectral library for use in data‐independent mass spectrometry
Publisher: Wiley
Date: 21-08-2021
Oncogenic B-RAFV600E Signaling Induces the T-Box3 Transcriptional Repressor to Repress E-Cadherin and Enhance Melanoma Cell Invasion
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1038/JID.2012.421
Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis
Publisher: Springer Science and Business Media LLC
Date: 02-07-2015
Early-life sun exposure and risk of melanoma before age 40 years
Publisher: Springer Science and Business Media LLC
Date: 07-04-2011
DOI: 10.1007/S10552-011-9762-3
Abstract: To examine associations between early-life sun exposure and risk of invasive cutaneous melanoma diagnosed between ages 18 and 39 years. Data were analysed from 606 cases and 481 controls from the Australian Melanoma Family Study, a population-based, case-control-family study. Self- and parent-reported sun exposure was collected by interview. Odds ratios (OR) were estimated using unconditional logistic regression, adjusted for potential confounders. Self-reported childhood total sun exposure was not associated with melanoma overall, but was positively associated with melanoma diagnosed at 18-29 years of age (OR for highest vs. lowest quartile: 3.21, 95% confidence intervals (CI) 1.38-7.44 P (trend) 0.02 P (interaction) by age group 0.09). Analyses restricted to participants whose self-reported sun exposure was concordant with that recalled by their parents gave an OR for the highest versus lowest tertile of childhood total sun exposure of 2.28 (95% CI 1.03-5.04 P (trend) 0.05), and for any versus no severe childhood sunburn of 2.36 (95% CI 1.05-5.31). The association of self-reported severe sunburn with melanoma was evident only in people who tended to tan rather than burn and in people who had few nevi. The association of early-life sun exposure with early-onset melanoma is influenced by host factors.
Is MSH2 a breast cancer susceptibility gene?
Publisher: Springer Science and Business Media LLC
Date: 06-10-2008
DOI: 10.1007/S10689-007-9162-8
Abstract: Mutations in the DNA mismatch repair gene MSH2 lead to increased replication error and microsatellite instability and account for a substantial proportion of hereditary non-polyposis colorectal cancer (Lynch syndrome). A recent international collaborative genome-wide linkage scan (GWS) for breast cancer susceptibility loci found some evidence for there being a breast cancer susceptibility gene in a genomic region on chromosome 2p close to MSH2. We sought to investigate the possibility that mutations in MSH2 might explain the multiple cases of breast cancer in some families that were included in the international GWS. DNA s les from the affected probands of 59 multiple-case breast cancer families, many of whom gave LOD scores >0.5 in the MSH2 region, were screened for large genomic alterations in MSH2 via the Multiplex Ligation-dependent Probe Amplification (MLPA) assay and for coding region mutations via exonic sequencing. Several of the families also contained cases of colorectal cancer in addition to breast cancer and had been included in the GWS that had identified a positive LOD score on chromosome 2p. Using MLPA, c.1236C > T was identified in one proband but this variant was not predicted to create an alternate acceptor/donor site within exon 7 MSH2 using in silico analyses. A c.1734T > C was identified in a second proband via exonic sequencing but testing of the variant in other family members did not support segregation of this variant with disease. Extensive screening of 59 multiple-case breast cancer families did not identify any coding region mutations or larger genomic alterations in MSH2 that might implicate MSH2 as a breast cancer susceptibility gene.
Homologous recombination DNA repair defects in PALB2-associated breast cancers
Publisher: Springer Science and Business Media LLC
Date: 08-08-2019
DOI: 10.1038/S41523-019-0115-9
Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 ( PALB2 ) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2 -associated breast cancers (BCs), and whether PALB2 -associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2 -associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH ( n = 11) or second somatic mutations ( n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2 -associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2 -associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2 -associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.
Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes
Publisher: Springer Science and Business Media LLC
Date: 2020
Combined cyclophosphamide, adriamycin and cis-platinum in advanced ovarian cancer resistant to chlorambucil and cis-platinum
Publisher: Elsevier BV
Date: 06-1985
DOI: 10.1016/0090-8258(85)90255-0
Abstract: Seventeen patients with advanced ovarian adenocarcinoma recurring or progressing after prior treatment with chlorambucil and cis-platinum were treated with cyclophosphamide, adriamycin, and cis-platinum (CAP) every 3 weeks. In seven patients there was objective tumor response (41%) with a median response duration of 7.6 months and a survival advantage over nonresponders. Patients whose tumors had previously responded to chlorambucil or cis-platinum were less likely to respond to CAP than those who had not responded. Myelosuppression was the main toxicity, febrile neutropenia occurring after 8% of treatments.
Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images
Publisher: Elsevier BV
Date: 04-2018
Doctors' recognition and management of melanoma patients' risk: An Australian population-based study
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.CANEP.2016.09.006
Abstract: Guidelines recommend that health professionals identify and manage in iduals at high risk of developing melanoma, but there is limited population-based evidence demonstrating real-world practices. A population-based, observational study was conducted in the state of New South Wales, Australia to determine doctors' knowledge of melanoma patients' risk and to identify factors associated with better identification and clinical management. Data were analysed for 1889 patients with invasive, localised melanoma in the Melanoma Patterns of Care study. This study collected data on all melanoma diagnoses notified to the state's cancer registry during a 12-month period from 2006 to 2007, as well as questionnaire data from the doctors involved in their care. Three-quarters (74%) of patients had doctors who were aware of their risk factor status with respect to personal and family history of melanoma and the presence of many moles. Doctors working in general practice, skin cancer clinics and dermatology settings had better knowledge of patients' risk factors than plastic surgeons. Doctors were 15% more likely to know the family history of younger melanoma patients (<40years) than of those ≥80 years (95% confidence interval 4-26%). Early detection-related follow-up advice was more likely to be given to younger patients, by doctors aware of their patients' risk status, by doctors practising in plastic surgery, dermatology and skin cancer clinic settings, and by female doctors. Both patient-related and doctor-related factors were associated with doctors' recognition and management of melanoma patients' risk and could be the focus of strategies for improving care.
Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549709.V1
Abstract: Abstract Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation uveal melanoma occurs in the eyes mucosal melanoma occurs in internal mucous membranes and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes. Significance: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-12-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2711 /a /i /
Selective loss of wild-type p16 INK4a expression in human nevi
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1038/JID.2011.197
Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families
Publisher: Elsevier BV
Date: 12-2017
The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma
Publisher: Elsevier BV
Date: 06-2018
Development of melanoma clinical quality indicators for the Australian melanoma clinical outcomes registry (MelCOR ): A modified Delphi study
Publisher: Wiley
Date: 29-04-2022
DOI: 10.1111/AJD.13848
Abstract: Clinical quality registries aim to identify significant variations in care and provide anonymised feedback to institutions to improve patient outcomes. Thirty‐six Australian organisations with an interest in melanoma, raised funds through three consecutive Melanoma Marches, organised by Melanoma Institute Australia, to create a national Melanoma Clinical Outcomes Registry (MelCOR). This study aimed to formally develop valid clinical quality indicators for the diagnosis and early management of cutaneous melanoma as an important step in creating the registry. Potential clinical quality indicators were identified by examining the literature, including Australian and international melanoma guidelines, and by consulting with key melanoma and registry opinion leaders. A modified two‐round Delphi survey method was used, with participants invited from relevant health professions routinely managing melanoma as well as relevant consumer organisations. Nineteen participants completed at least one round of the Delphi process. 12 of 13 proposed clinical quality indictors met the validity criteria. The clinical quality indicators included acceptable biopsy method, appropriate excision margins, standardised pathology reporting, indications for sentinel lymph node biopsy, and involvement of multidisciplinary care and referrals. This study provides a multi‐stakeholder consensus for important clinical quality indicators that define optimal practice that will now be used in the Australian Melanoma Clinical Outcomes Registry (MelCOR).
eMelanoBase: an online locus-specific variant database for familial melanoma.
Publisher: Hindawi Limited
Date: 20-12-2003
DOI: 10.1002/HUMU.10149
Abstract: A proportion of melanoma-prone in iduals in both familial and non-familial contexts has been shown to carry inactivating mutations in either CDKN2A or, rarely, CDK4. CDKN2A is a complex locus that encodes two unrelated proteins from alternately spliced transcripts that are read in different frames. The alpha transcript (exons 1alpha, 2, and 3) produces the p16INK4A cyclin-dependent kinase inhibitor, while the beta transcript (exons 1beta and 2) is translated as p14ARF, a stabilizing factor of p53 levels through binding to MDM2. Mutations in exon 2 can impair both polypeptides and insertions and deletions in exons 1alpha, 1beta, and 2, which can theoretically generate p16INK4A-p14ARF fusion proteins. No online database currently takes into account all the consequences of these genotypes, a situation compounded by some problematic previous annotations of CDKN2A-related sequences and descriptions of their mutations. As an initiative of the international Melanoma Genetics Consortium, we have therefore established a database of germline variants observed in all loci implicated in familial melanoma susceptibility. Such a comprehensive, publicly accessible database is an essential foundation for research on melanoma susceptibility and its clinical application. Our database serves two types of data as defined by HUGO. The core dataset includes the nucleotide variants on the genomic and transcript levels, amino acid variants, and citation. The ancillary dataset includes keyword description of events at the transcription and translation levels and epidemiological data. The application that handles users' queries was designed in the model-view-controller architecture and was implemented in Java. The object-relational database schema was deduced using functional dependency analysis. We hereby present our first functional prototype of eMelanoBase. The service is accessible via the URL www.wmi.usyd.edu.au:8080/melanoma.html.
Development and validation of a targeted gene sequencing panel for application to disparate cancers
Publisher: Springer Science and Business Media LLC
Date: 19-11-2019
DOI: 10.1038/S41598-019-52000-3
Abstract: Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA s les were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein ( AIP ) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of % and precision of %. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.
Rare Variant, Gene-Based Association Study of Hereditary Melanoma Using Whole-Exome Sequencing
Publisher: Oxford University Press (OUP)
Date: 03-06-2017
DOI: 10.1093/JNCI/DJX083
Recurrent inactivating RASA2 mutations in melanoma
Publisher: Springer Science and Business Media LLC
Date: 26-10-2015
DOI: 10.1038/NG.3427
MC1R genotypes and risk of melanoma before age 40 years: A population-based case-control-family study
Publisher: Wiley
Date: 30-01-2012
DOI: 10.1002/IJC.27357
Protocol for a within-trial economic evaluation of a psychoeducational intervention tailored to people at high risk of developing a second or subsequent melanoma
Publisher: BMJ
Date: 10-2016
Publisher Correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways
Publisher: Springer Science and Business Media LLC
Date: 14-01-2019
DOI: 10.1038/S41467-018-08078-W
Abstract: The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.
Genomic and proteomic findings in early melanoma and opportunities for early diagnosis
Publisher: Wiley
Date: 28-11-2022
DOI: 10.1111/EXD.14705
Abstract: Overdiagnosis of early melanoma is a significant problem. Due to subtle unique and overlapping clinical and histological criteria between pigmented lesions and the risk of mortality from melanoma, some benign pigmented lesions are diagnosed as melanoma. Although histopathology is the gold standard to diagnose melanoma, there is a demand to find alternatives that are more accurate and cost‐effective. In the current “omics” era, there is gaining interest in biomarkers to help diagnose melanoma early and to further understand the mechanisms driving tumor progression. Genomic investigations have attempted to differentiate malignant melanoma from benign pigmented lesions. However, genetic biomarkers of early melanoma diagnosis have not yet proven their value in the clinical setting. Protein biomarkers may be more promising since they directly influence tissue phenotype, a result of by‐products of genomic mutations, posttranslational modifications and environmental factors. Uncovering relevant protein biomarkers could increase confidence in their use as diagnostic signatures. Currently, proteomic investigations of melanoma progression from pigmented lesions are limited. Studies have previously characterised the melanoma proteome from cultured cell lines and clinical s les such as serum and tissue. This has been useful in understanding how melanoma progresses into metastasis and development of resistance to adjuvant therapies. Currently, most studies focus on metastatic melanoma to find potential drug therapy targets, prognostic factors and markers of resistance. This paper reviews recent advancements in the genomics and proteomic fields and reports potential avenues, which could help identify and differentiate melanoma from benign pigmented lesions and prevent the progression of melanoma.
Tumour procurement, DNA extraction, coverage analysis and optimisation of mutation-detection algorithms for human melanoma genomes
Publisher: Elsevier BV
Date: 12-2015
Implementation of patient-reported outcome measures and patient-reported experience measures in melanoma clinical quality registries: a systematic review
Publisher: BMJ
Date: 02-2021
DOI: 10.1136/BMJOPEN-2020-040751
Abstract: To identify patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) in clinical quality registries, for people with cutaneous melanoma, to inform a new Australian Melanoma Clinical Outcomes Registry and describe opportunities and challenges of routine PROM/PREM collection, especially in primary care. Systematic review. Which PROMs and PREMs are used in clinical quality registries for people with cutaneous melanoma, how they are collected, frequency of collection, participant recruitment methods and funding models for each registry. 1134 studies were identified from MEDLINE, PreMEDLINE, Embase, PsychInfo, Cochrane Database of Abstracts of Reviews of Effects databases and TUFTS Cost-Effectiveness Analysis Registry, alongside grey literature, from database inception to 5th February 2020. Following screening, 14 studies were included, identifying four relevant registries: Dutch Melanoma Registry, Adelphi Real-World Disease-Specific Programme (Melanoma), Patient-Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship Registry, and Cancer Experience Registry. These used seven PROMs: EuroQol-5 Dimensions, Functional Assessment of Cancer-General (FACT-G) and FACT-Melanoma (FACT-M), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Cancer 30 (EORTC QLQ-C30), Fatigue Assessment Scale Hospital Anxiety and Depression Scale, Patient-Reported Outcome Measures Information System-29 and one PREM EORTC QLQ-Information Module 26. PROMs/PREMs in registries were reported to improve transparency of care facilitate clinical auditing for quality assessment enable cost-effectiveness analyses and create large-scale research platforms. Challenges included resource burden for data entry and potential collection bias toward younger, more affluent respondents. Feedback from patients with melanoma highlighted the relevance of PROMs/PREMs in assessing patient outcomes and patient experiences. Clinical registries indicate PROMs/PREMs for melanoma care can be incorporated and address important gaps, however cost and collection bias may limit generalisability. CRD42018086737.
The Prognostic Significance of Low-Frequency Somatic Mutations in Metastatic Cutaneous Melanoma
Publisher: Frontiers Media SA
Date: 04-01-2019
Polyunsaturated fatty acids and risk of melanoma: A M endelian randomisation analysis
Publisher: Wiley
Date: 05-03-2018
DOI: 10.1002/IJC.31334
Abstract: Melanoma is the deadliest form of skin cancer, mainly affecting populations of European ancestry. Some observational studies suggest that particular diets reduce melanoma risk, putatively through an increase in polyunsaturated fatty acid (PUFA) consumption. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To date, a randomized controlled trial has not been carried out to examine the relationship between PUFAs and melanoma. Hence, we performed a Mendelian randomisation (MR) study to evaluate the link between PUFAs and melanoma. To perform MR, we used summary results from the largest risk genome-wide association study (GWAS) meta-analysis of melanoma, consisting of 12,874 cases and 23,203 controls. As instrumental variables we selected SNPs associated with PUFA levels from a GWAS meta-analysis of PUFA levels, from the CHARGE consortium. We used the inverse variance weighted method to estimate a causal odds ratio. To aid interpretation, we established a benchmark "large" predicted change in PUFAs in which, for ex le, an increase in docosahexaenoic acid (DPA) of 0.17 units (equal to 1 standard deviation) moves a person from the 17
The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
Publisher: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1038/S41523-019-0127-5
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1 , BRCA2 , PALB2 , ATM , and CHEK2 are associated with breast cancer risk. FANCM , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2 . These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM −/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79 P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM :p.Arg658* and found that also FANCM :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96 P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM -associated tumors.
Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT
Publisher: Elsevier BV
Date: 08-2019
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-0001
DOI: 10.1158/2159-8290.22541635.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2202
DOI: 10.1158/2159-8290.22541641.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Patterns of metastases in familial and non-familial melanoma
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2003
DOI: 10.1097/00008390-200302000-00017
Abstract: Family history is a strong risk factor for the development of primary melanoma and is associated in a subset with inherited mutations in melanoma susceptibility genes. This study sought to determine whether differences in metastatic pattern exist between patients with a positive family history (FH+) and those with a negative family history (FH-). Such differences could have importance for clinical management and in the determination of the function of both known and putative melanoma susceptibility genes. A retrospective, nested case-controlled study was performed. Of the FH+ cohort (n = 38), 26 were from kindreds with two histologically verified affected first-degree relatives and 12 were from kindreds with three or more affected members, at least two of whom were first-degree relatives. Three FH- controls from the Sydney Melanoma Unit database were matched to each case for age, sex, stage at diagnosis, number of primary melanomas and year of diagnosis (n = 114). There were no statistically significant differences between the two groups with regard to overall survival from initial diagnosis (FH+, 57.4 months FH-, 50.0 months P = 0.99), median survival from time of first metastasis (FH+, 15.4 months FH-, 15.9 months P = 0.94), or median disease-free interval (FH+, 26.4 months FH-, 29.7 months P = 0.73). On multivariate conditional logistic regression analysis, there was no statistically significant difference between the two groups in the probability of developing initial metastases or of ever developing metastases at specific sites. Survival, disease-free interval and distribution of metastatic sites are similar in both familial and non-familial melanoma. Genetic susceptibility for melanoma may lower the threshold for entering an otherwise common molecular pathway for tumour development and evolution.
Identification of new prognostic biomarkers for Stage III metastatic melanoma patients
Publisher: Informa UK Limited
Date: 09-2013
DOI: 10.4161/ONCI.25564
Imatinib Disposition and ABCB1 (MDR1, P-Glycoprotein) Genotype
Publisher: Springer Science and Business Media LLC
Date: 09-05-2007
Abstract: The aim of this study was to explore the impact of in idual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these in iduals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.
Cross-Platform Omics Prediction procedure: a game changer for implementing precision medicine in patients with stage-III melanoma
Publisher: Cold Spring Harbor Laboratory
Date: 09-12-2020
DOI: 10.1101/2020.12.09.415927
Abstract: There is no consensus methodology that can account for the variation in omics signatures when they are acquired across different platforms and times. This poses a significant barrier to the implementation of valuable biomarkers into clinical practice. We present a novel procedure (Cross-Platform Omics Prediction) that accounts for these variations and demonstrate its utility in three risk models for different diseases that is suitable for prospective and multi-centre clinical implementation.
Recurrent hotspot SF3B1 mutations at codon 625 in vulvovaginal mucosal melanoma identified in a study of 27 Australian mucosal melanomas
Publisher: Impact Journals, LLC
Date: 29-01-2019
Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial
Publisher: Elsevier BV
Date: 12-2021
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541623.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541617.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Prevalence and predictors of germline CDKN2A mutations for melanoma cases from Australia, Spain and the United Kingdom
Publisher: Springer Science and Business Media LLC
Date: 20-11-2014
Distinct molecular profiles and immunotherapy treatment outcomes of V600E and V600K BRAF-mutant melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2019
DOI: 10.1158/1078-0432.CCR-18-1680
Abstract: BRAF V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to BRAFi±MEKi. We investigated mechanisms for this and explored whether genotype affects response to immunotherapy. Pretreatment formalin-fixed paraffin-embedded tumors from patients treated with BRAFi±MEKi underwent gene expression profiling and DNA sequencing. Molecular results were validated using The Cancer Genome Atlas (TCGA) data. An independent cohort of V600E/K patients treated with anti–PD-1 immunotherapy was examined. Baseline tissue and clinical outcome with BRAFi±MEKi were studied in 93 patients (78 V600E, 15 V600K). V600K patients had numerically less tumor regression (median, −31% vs. −52%, P = 0.154) and shorter progression-free survival (PFS median, 5.7 vs. 7.1 months, P = 0.15) compared with V600E. V600K melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6, confirmed with TCGA data (116 V600E, 17 V600K). Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E. Higher mutational load was observed in V600K, with a higher proportion of mutations in PIK3R1 and tumor-suppressor genes. In patients treated with anti–PD-1, V600K (n = 19) had superior outcomes than V600E (n = 84), including response rate (53% vs. 29%, P = 0.059), PFS (median, 19 vs. 2.7 months, P = 0.049), and overall survival (20.4 vs. 11.7 months, P = 0.081). BRAF V600K melanomas appear to benefit less from BRAFi±MEKi than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy.
Uncovering the complex relationship between balding, testosterone and skin cancers in men
Publisher: Springer Science and Business Media LLC
Date: 03-10-2023
Author Correction: Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples
Publisher: Springer Science and Business Media LLC
Date: 30-11-2020
DOI: 10.1038/S41467-020-20128-W
Abstract: Correction to this paper has been published: 0.1038/s41467-020-20128-w
A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples
Publisher: Elsevier BV
Date: 04-2018
Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization
Publisher: Springer Science and Business Media LLC
Date: 15-06-2000
Abstract: The INK4a/ARF locus encodes two distinct tumour suppressors, p16INK4a and p14ARF, that regulate cell cycle progression via the pRB and p53 pathways, respectively. The ARF protein inhibits hdm2 activity, leading to the stabilization of the p53 tumour suppressor and cell cycle inhibition. The amino-terminal domain of human p14ARF and of the mouse homologue, p19ARF, is sufficient for these effects. This domain is also sufficient for the nucleolar localization of the mouse ARF protein. In contrast, we show that the human ARF protein requires two arginine rich domains, one in the amino- and the other in the carboxy-terminus, for nucleolar targeting. The amino-terminal nucleolar-targeting domain of p14ARF is also important for ARF-hdm2 binding and cell cycle inhibition. The carboxy-terminal p14ARF nucleolar localization domain lies within the shared INK4a/ARF exon 2, and is mutated in a small number of melanoma-prone kindreds. The INK4a/ARF exon2-mutations could affect the function of both the p16INK4a and p14ARF tumour suppressors. Oncogene (2000).
Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer
Publisher: Elsevier BV
Date: 04-2018
Analysis of cancer risk and BRCA1 and BRCA2mutation prevalence in the kConFab familial breast cancer resource
Publisher: Springer Science and Business Media LLC
Date: 02-2006
DOI: 10.1186/BCR1377
Development and external validation study of a melanoma risk prediction model incorporating clinically assessed naevi and solar lentigines
Publisher: Oxford University Press (OUP)
Date: 22-09-2020
DOI: 10.1111/BJD.18411
A Dual-Antigen Enzyme-Linked Immunosorbent Assay Allows the Assessment of Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Seroprevalence in a Low-Transmission Setting
Publisher: Oxford University Press (OUP)
Date: 03-10-2021
Abstract: Estimates of seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies have been h ered by inadequate assay sensitivity and specificity. Using an enzyme-linked immunosorbent assay–based approach that combines data about immunoglobulin G responses to both the nucleocapsid and spike receptor binding domain antigens, we show that excellent sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (95% Confidence Interval, 0–1.15%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay.
Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium
Publisher: Proceedings of the National Academy of Sciences
Date: 15-01-2002
Abstract: The known susceptibility genes for breast cancer, including BRCA1 and BRCA2, only account for a minority of the familial aggregation of the disease. A recent study of 77 multiple case breast cancer families from Scandinavia found evidence of linkage between the disease and polymorphic markers on chromosome 13q21. We have evaluated the contribution of this candidate “BRCA3” locus to breast cancer susceptibility in 128 high-risk breast cancer families of Western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion (α) of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. [(2000) Proc. Natl. Acad. Sci. USA 97, 9603–9608], was 0 (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result (α = 0, upper 95% confidence limit 0.18). The proportion of linked families reported by Kainu et al. (0.65) is excluded with a high degree of confidence in our dataset [heterogeneity logarithm of odds (HLOD) at α = 0.65 was −11.0]. We conclude that, if a susceptibility gene does exist at this locus, it can only account for a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer.
The association of dermatologist demographic density with melanoma survival in New South Wales, Australia
Publisher: Wiley
Date: 24-06-2023
DOI: 10.1111/AJD.14113
High- and average-risk individuals' beliefs about, and perceptions of, malignant melanoma: an Australian perspective
Publisher: Wiley
Date: 2008
DOI: 10.1002/PON.1230
Abstract: Despite expanding knowledge regarding the genetics of melanoma, there have been few attempts to define the psychosocial experiences of in iduals with a family history of this disease. This study explored the ways in which in iduals at varying levels of risk perceive, and respond to, melanoma. Forty semi-structured interviews were undertaken with affected (n = 20) and unaffected (n = 20) in iduals with or without a family history of melanoma. Data were analysed for potential thematic differences between risk groups, genders, and intentions to pursue genetic testing for melanoma risk. Overall, participants with a family history were in acceptance of their increased risk status and had developed ways of coping without major disruption to their daily lives. However, some participants expressed ambiguity regarding the causes of melanoma and the effectiveness of health behaviours such as sun protection. Major thematic patterns identified for those intending to pursue genetic testing were: negative emotional associations with melanoma an emphasis on screening and sun avoidance, but not sun protection and heightened perceptions of personal susceptibility to melanoma. In contrast, thematic patterns identified for those likely to decline testing were: ready access to stories of melanoma survival and an emphasis on the causal role of sun exposure, whilst still believing that genetic factors may contribute to melanoma susceptibility. Compared to males, females reported a greater tendency to completely avoid the sun in order to reduce their melanoma risk. The data provide preliminary evidence for the importance of identifying misconceptions that may impede informed decision-making about genetic testing for melanoma risk.
Risk factors for melanoma by anatomical site: an evaluation of aetiological heterogeneity*
Publisher: Oxford University Press (OUP)
Date: 18-02-2021
DOI: 10.1111/BJD.19705
Abstract: Melanoma aetiology has been proposed to have two pathways, which are determined by naevi and type of sun exposure and related to the anatomical site where melanoma develops. We examined associations with melanoma by anatomical site for a comprehensive set of risk factors including pigmentary and naevus phenotypes, ultraviolet radiation exposure and polygenic risk. We analysed harmonized data from 2617 people with incident first invasive melanoma and 975 healthy controls recruited through two population-based case-control studies in Australia and the UK. Questionnaire data were collected by interview using a single protocol, and pathway-specific polygenic risk scores were derived from DNA s les. We estimated adjusted odds ratios using unconditional logistic regression that compared melanoma cases at each anatomical site with all controls. When cases were compared with control participants, there were stronger associations for many naevi vs. no naevi for melanomas on the trunk, and upper and lower limbs than on the head and neck (P-heterogeneity < 0·001). Very fair skin (vs. olive/brown skin) was more weakly related to melanoma on the trunk than to melanomas at other sites (P-heterogeneity = 0·04). There was no significant difference by anatomical site for polygenic risk. Increased weekday sun exposure was positively associated with melanoma on the head and neck but not on other sites. We found evidence of aetiological heterogeneity for melanoma, supporting the dual pathway hypothesis. These findings enhance understanding of risk factors for melanoma and can guide prevention and skin examination education and practices.
Pan-cancer analysis of whole genomes
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1969-6
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution in acral melanoma, for ex le, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 analyses timings and patterns of tumour evolution 7 describes the erse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 and evaluates a range of more-specialized features of cancer genomes 8,10–18 .
Mutation load in melanoma is affected by MC1R genotype.
Publisher: Wiley
Date: 03-2017
DOI: 10.1111/PCMR.12571
Abstract: Whole-genome sequencing of matched germline and tumour pairs in a well-characterized cohort of melanoma patients allowed investigation of associations between melanoma body site, age at melanoma onset and MC1R variant status with overall mutation burden and specific base pair changes observed in the corresponding melanoma. We observed statistically significant associations between mutation burden in melanoma and body site, age at onset and MC1R genotype, for both ultraviolet radiation (UVR) signature changes (C>T and CC>TT) and non-UVR base pair substitutions, as well as with overall variant load.
An independent external validation of melanoma risk prediction models using the Australian Melanoma Family Study
Publisher: Oxford University Press (OUP)
Date: 02-2021
DOI: 10.1111/BJD.19706
Mutations in the INK4a/ARF Melanoma Susceptibility Locus Functionally Impair p14ARF
Publisher: Elsevier BV
Date: 11-2001
Expression Analysis of a Tyrosinase Promoter Sequence in Zebrafish
Publisher: Wiley
Date: 05-03-2003
DOI: 10.1034/J.1600-0749.2003.00002.X
Abstract: Sequence comparisons and functional analysis of the 5' upstream regions of tyrosinase genes have revealed the importance of cis-regulatory elements acting to control the spatiotemporal expression of tyrosinase in the melanocytes and retinal pigmented epithelium of developing embryos. To date there are no reports addressing the control of tyrosinase gene transcription in zebrafish, a vertebrate model organism of increasing importance. To exploit the tyrosinase gene as a marker in zebrafish we set out to clone its promoter and analyse its regulation during embryogenesis. Amplification of a zebrafish tyrosinase complementary DNA fragment by reverse transcriptase polymerase chain reaction allowed us to isolate and sequence a 1041 nt genomic DNA fragment that includes a transcription initiation site and 73 nt of the open reading frame. Bioinformatic analysis of this genomic sequence revealed five E-box motifs, including one CATGTG type E-box present in a putative initiation region. These are conserved positive regulatory elements in vertebrate tyrosinase promoters. We show that a region of 814 nt upstream from the translation start site of the zebrafish tyrosinase gene can drive expression in retinal pigmented epithelium in transiently transgenic zebrafish embryos but that its activity is not restricted to melanin-producing cells. This region is unable to drive transcription in human melanoma cell lines. Ectopic expression from this zebrafish tyrosinase promoter fragment is probably due to the absence of positive and negative cis-regulatory elements, such as a tyrosinase distal element, which is known to function as a pigment cell-specific enhancer.
A genome wide linkage search for breast cancer susceptibility genes
Publisher: Wiley
Date: 30-03-2006
DOI: 10.1002/GCC.20330
RAD51B in Familial Breast Cancer
Publisher: Public Library of Science (PLoS)
Date: 05-05-2016
Differential distribution improves gene selection stability and has competitive classification performance for patient survival
Publisher: Oxford University Press (OUP)
Date: 17-05-2016
DOI: 10.1093/NAR/GKW444
Predicting functional significance of cancer-associated p16INK4a mutations in CDKN2A
Publisher: Hindawi Limited
Date: 25-03-2010
DOI: 10.1002/HUMU.21245
Abstract: Inherited mutations affecting the INK4a/ARF locus (CDKN2A) are associated with melanoma susceptibility in 40% of multiple case melanoma families. Over 60 different germline INK4a/ARF mutations have been detected in more than 190 families worldwide. The majority of these alterations are missense mutations affecting p16(INK4a), and only 25% of these have been functionally assessed. There is therefore a need for an accurate and rapid assay to determine the functional significance of p16(INK4a) mutations. We reviewed the performance of several in vivo functional assays that measure critical aspects of p16(INK4a) function, including subcellular location, CDK binding and cell cycle inhibition. In this report the function of 28 p16(INK4a) variants, many associated with melanoma susceptibility were compared. We show that assessment of CDK4 binding and subcellular localization can accurately and rapidly determine the functional significance of melanoma-associated p16(INK4a) mutations. p16(INK4a)-CDK6 binding affinity was unhelpful, as no disease-associated mutation showed reduced CDK6 affinity while maintaining the ability to bind CDK4. Likewise, in silico analyses did not contribute substantially, with only 12 of 25 melanoma-associated missense variants consistently predicted as deleterious. The ability to determine variant functional activity accurately would identify disease-associated mutations and facilitate effective genetic counselling of in iduals at high risk of melanoma.
Differential expression of p16INK4a and p16β transcripts in B-lymphoblastoid cells from members of hereditary melanoma families without CDKN2A exon mutations
Publisher: Springer Science and Business Media LLC
Date: 31-07-1997
Abstract: Mutations in the CDKN2A (p16INK4a) tumour suppressor gene on chromosome 9p21 are associated with inherited predisposition to melanoma, yet some 9p-linking hereditary melanoma families show no mutations in this gene. Splicing of CDKN2A exons 2 and 3 to an alternative first exon produces a transcript (p16beta) encoding a protein with cell cycle regulatory properties. We have analysed allele-specific expression levels of both the p16INK4a and p16beta transcripts in B-lymphoblastoid cells from 18 members of hereditary melanoma kindreds including four unrelated control in iduals. In 15 of the 18 in iduals examined, steady-state levels of each transcript either originated equally from each parental chromosome, or one parental chromosome was dominant for both transcripts. However, in three affected members of two 9p-linking hereditary melanoma kindreds, without exonic CDKN2A mutations, this pattern of coordinate expression was disrupted. In these in iduals there was underexpression of the p16beta transcript, relative to the p16INK4a transcript, from the chromosome segregating with disease susceptibility. Loss of coordinate expression of the p16INK4a and p16beta transcripts may be an alternative genetic basis for melanoma susceptibility in certain 9p-linking kindreds.
Proteomic phenotyping of metastatic melanoma reveals putative signatures of MEK inhibitor response and prognosis
Publisher: Springer Science and Business Media LLC
Date: 17-08-2018
The COMPASs Study: Community Preferences for Prostate cAncer Screening. Protocol for a quantitative preference study: Figure 1
Publisher: BMJ
Date: 2012
Associations of pigmentary and naevus phenotype with melanoma risk in two populations with comparable ancestry but contrasting levels of ambient sun exposure
Publisher: Wiley
Date: 07-06-2019
DOI: 10.1111/JDV.15680
Efficiency of Detecting New Primary Melanoma Among Individuals Treated in a High-risk Clinic for Skin Surveillance
Publisher: American Medical Association (AMA)
Date: 05-2021
Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.CCELL.2018.07.001
Abstract: Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal s les. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal s les on average, we identified ≈930 exon-exon junctions ("neojunctions") in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor s les, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor s le that are also predicted major histocompatibility complex-I binders ("putative neoantigens").
Immunofluorescent quantification of ribonucleotide reductase M1 subunit and correlation with DNA content by flow cytometry
Publisher: Wiley
Date: 09-1987
Abstract: The cytoplasmic enzyme ribonucleotide reductase is essential for DNA synthesis, and its activity is strongly correlated with cellular proliferation. This paper describes a flow cytometric technique for the simultaneous measurement of DNA content and the M1 subunit of ribonucleotide reductase. Data are presented for cycling cultured human leukemic lymphoblasts in which M1 is constitutively expressed, and peripheral blood lymphocytes in which it is only detectable with certainty after mitogen stimulation. The choice of fixation procedure strongly influenced the amount of M1 subunit detected. Paraformaldehyde (PF) at concentrations of 2% (w/v in PBS) or greater provided optimal results. Fixation at 37 degrees C was significantly more effective in preserving M1 than fixation at room temperature or 4 degrees C. These variables are shown to have affected cytoplasmic retention during postfixation processing. Their relevance to the flow cytometric measurement of other intracellular components by this procedure are discussed.
Meta-Analysis Combining New and Existing Data Sets Confirms that the TERT-CLPTM1L Locus Influences Melanoma Risk
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1038/JID.2011.322
Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours
Publisher: Springer Science and Business Media LLC
Date: 15-05-2020
DOI: 10.1038/S41467-020-16276-8
Abstract: Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation ( GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX ). We identify three other significantly mutated genes ( TP53 , RPL5 and CENPE ).
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541617
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Poor Adherence to National Clinical Management Guidelines
Publisher: Springer Science and Business Media LLC
Date: 25-05-2017
DOI: 10.1245/S10434-017-5890-7
Abstract: Standardization of the clinical management of melanoma through the formulation of national guidelines, based on interpretation of the existing evidence and consensus expert opinion, seeks to improve quality of care however, adherence to national guidelines has not been well studied. A population-based, cross-sectional study of the clinical management of all patients with newly notified primary melanomas in the state of New South Wales, Australia, during 2006/2007 was conducted using cancer registry identification and questionnaires completed by treating physicians. Surgical margin guidelines were adhered to in 35% of cases 45% were over treated and 21% were undertreated. Factors independently associated with non-concordance on multivariate analysis were lower Breslow thickness, lower socio-economic status of the physician's practice location, older physician age, lower physician caseload, and physicians who biopsied the lesion and then referred for definitive management. Complications were not related to over- or under-treatment on multivariate analysis (p = 0.72). Sentinel lymph node biopsy was performed in 17% of patients with invasive melanoma, with the main determinant for selection being a Breslow thickness >0.75 mm. The low level of concordance with national guidelines for surgical management of melanoma resulted in overtreatment of many patients. However, a fifth of patients were undertreated, which is likely to have resulted in increased locoregional recurrence rates. The better concordance achieved by physicians treating >30 melanomas per year suggests that a minimum caseload threshold for physicians treating melanoma patients would be desirable. High guideline concordance will ensure patients receive optimal care and minimize morbidity and health service costs.
Cancer Vaccines in Phase II/III Clinical Trials: State of the Art and Future Perspectives
Publisher: Bentham Science Publishers Ltd.
Date: 2011
DOI: 10.2174/156800911793743664
Abstract: The topic of this review covers a very important branch of cancer research, cancer vaccination. The growing knowledge in tumor immunology has evolved rapidly, starting from nonspecific generic stimulation of the immune system to more specific approaches based on the availability of tumor antigens. The review covers molecular and cell biology, and pharmaceutical technology of cancer vaccines. Particularly, it is aimed at highlighting the results of cancer vaccines from phase II and III clinical trials, an issue that is of relevance to better understand how cancer vaccines can successfully complement antitumor therapy, including conventional chemotherapy and the recently developed target-based drugs.
Telomere sequence content can be used to determine ALT activity in tumours
Publisher: Oxford University Press (OUP)
Date: 30-04-2018
DOI: 10.1093/NAR/GKY297
MicroRNA and mRNA expression profiling in metastatic melanoma reveal associations with BRAF mutation and patient prognosis
Publisher: Wiley
Date: 05-01-2015
DOI: 10.1111/PCMR.12343
Abstract: The role of microRNAs (miRNAs) in melanoma is unclear. We examined global miRNA expression profiles in fresh-frozen metastatic melanomas in relation to clinical outcome and BRAF mutation, with validation in independent cohorts of tumours and sera. We integrated miRNA and mRNA information from the same s les and elucidated networks associated with outcome and mutation. Associations with prognosis were replicated for miR-150-5p, miR-142-3p and miR-142-5p. Co-analysis of miRNA and mRNA uncovered a network associated with poor prognosis (PP) that paradoxically favoured expression of miRNAs opposing tumorigenesis. These miRNAs are likely part of an autoregulatory response to oncogenic drivers, rather than drivers themselves. Robust association of miR-150-5p and the miR-142 duplex with good prognosis and earlier stage metastatic melanoma supports their potential as biomarkers. miRNAs overexpressed in association with PP in an autoregulatory fashion will not be suitable therapeutic targets.
Prevalence of asymptomatic SARS-CoV-2 infection in elective surgical patients in Australia: a prospective surveillance study.
Publisher: Wiley
Date: 2021
DOI: 10.1111/ANS.16564
Deoxyadenosine triphosphate as a mediator of deoxyguanosine toxicity in cultured T lymphoblasts
Publisher: American Society for Clinical Investigation
Date: 11-1986
DOI: 10.1172/JCI112710
The Melanoma care study: protocol of a randomised controlled trial of a psycho-educational intervention for melanoma survivors at high risk of developing new primary disease
Publisher: Springer Science and Business Media LLC
Date: 11-07-2015
Paracetamol inhibits replicative DNA synthesis and induces sister chromatid exchange and chromosomal aberrations by inhibition of ribonucleotide reductase
Publisher: Oxford University Press (OUP)
Date: 1990
Abstract: Effects of paracetamol have been studied in a hydroxyurea (HU)-resistant mouse mammary tumour cell line TA3H2, shown to overproduce the small subunit of ribonucleotide reductase. These TA3H2 cells were much more resistant than the TA3H (wild-type) cells towards the inhibitory effect of paracetamol on cell growth, IC50 0.55 mM paracetamol for the wild-type compared to 2.7 mM for the HU-resistant cells. The reduced cell growth was due to an inhibition of replicative DNA synthesis, judged from an increased percentage of cells in S-phase measured by flow cytometry. Furthermore, in the wild-type cells, the increase in the number of cells in S phase was already observed at 0.1 mM while in the HU-resistant cell line this effect was first seen at 3.0 mM paracetamol. HU inhibits ribonucleotide reductase by destroying a tyrosyl free radical located on the small subunit of the enzyme. By electron paramagnetic resonance we demonstrate that paracetamol added to crude cell extracts of HU-resistant cells also immediately destroys this radical. These results show that paracetamol reduces DNA synthesis by a specific inhibition of ribonucleotide reductase. A concentration-dependent induction of sister chromatid exchanges was found both with paracetamol (1.0-10 mM) and HU (0.3-3 mM) in wild-type cells whereas no such increase was observed in HU-resistant cells. Paracetamol (1 mM for 2 h) also increased the number of chromosomal aberrations CAs in wild-type cells (i.e. chromatid breaks and chromatid exchanges). The frequency of CAs was not increased in HU-resistant cells at paracetamol concentrations up to 10 mM.(ABSTRACT TRUNCATED AT 250 WORDS)
Meeting report from the 7th International Melanoma Congress, Sydney, November, 2010
Publisher: Wiley
Date: 22-12-2010
A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers
Publisher: Elsevier BV
Date: 04-2018
Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets
Publisher: Springer Science and Business Media LLC
Date: 18-07-2019
DOI: 10.1038/S41467-019-11107-X
Abstract: Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2 . Significantly mutated genes are NRAS , BRAF , NF1 , KIT , SF3B1 , TP53 , SPRED1 , ATRX , HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
TRIM16 inhibits proliferation and migration through regulation of interferon beta 1 in melanoma cells
Publisher: Impact Journals, LLC
Date: 30-10-2014
Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma
Publisher: Elsevier BV
Date: 05-2017
Abstract: Programmed death 1 (PD1) inhibitors are now a foundation of medical management of metastatic melanoma. This study sought to determine whether circulating tumour DNA (ctDNA) provides useful early response and prognostic information. We evaluated the relationship between pre-treatment and early on treatment ctDNA and outcome in melanoma patients treated with PD1 inhibitors alone or in combination with ipilimumab. ctDNA was detected in 40/76 patients (53%) at baseline, and correlated with stage, LDH levels, disease volume and ECOG performance. RECIST response was 72% (26/36) in group A (undetectable ctDNA at baseline), 77% (17/22) in group B (elevated ctDNA at baseline but undetectable within 12 weeks of therapy) and 6% (1/18) in group C (elevated ctDNA at baseline and remained elevated during treatment). The median PFS was not reached in groups A and B and was 2.7 months for group C [hazard ratio (HR) 0.09 P < 0.001 for group A versus C, and 0.16 P < 0.001 for group B versus C]. The median OS was not reached for groups A and B and was 9.2 months for group C (HR 0.02 P < 0.001 for group A versus C and 0.14 P < 0.001 for group B versus C). The poor outcome measures associated with group C remained significant in multivariate analysis adjusted for LDH, performance status, tumour stage and disease volume. The predictive value for ctDNA for response was confirmed in a separate validation cohort (n = 29, P < 0.01). Longitudinal assessment of ctDNA in metastatic melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumour response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis, and this may guide combination and sequencing of subsequent therapies.
Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541629.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas
Publisher: Elsevier BV
Date: 04-2018
FRAMe: Familial Risk Assessment of Melanoma-a risk prediction tool to guide CDKN2A germline mutation testing in Australian familial melanoma.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2020
DOI: 10.1007/S10689-020-00209-X
Abstract: Germline mutations in CDKN2A greatly increase risk of developing cutaneous melanoma. We have constructed a risk prediction model, Familial Risk Assessment of Melanoma (FRAMe), for estimating the likelihood of carrying a heritable CDKN2A mutation among Australian families, where the prevalence of these mutations is low. Using logistic regression, we analysed characteristics of 299 Australian families recruited through the Sydney site of GenoMEL (international melanoma genetics consortium) with at least three cases of cutaneous melanoma (in situ and invasive) among first-degree blood relatives, for predictors of the presence of a pathogenic CDKN2A mutation. The final multivariable prediction model was externally validated in an independent cohort of 61 melanoma kindreds recruited through GenoMEL Queensland. Family variables independently associated with the presence of a CDKN2A mutation in a multivariable model were number of in iduals diagnosed with melanoma under 40 years of age, number of in iduals diagnosed with more than one primary melanoma, and number of in iduals blood related to a melanoma case in the first degree diagnosed with any cancer excluding melanoma and non-melanoma skin cancer. The number of in iduals diagnosed with pancreatic cancer was not independently associated with mutation status. The risk prediction model had an area under the receiver operating characteristic curve (AUC) of 0.851 (95% CI 0.793, 0.909) in the training dataset, and 0.745 (95%CI 0.612, 0.877) in the validation dataset. This model is the first to be developed and validated using only Australian data, which is important given the higher rate of melanoma in the population. This model will help to effectively identify families suitable for genetic counselling and testing in areas of high ambient ultraviolet radiation. A user-friendly electronic nomogram is available at www.melanomarisk.org.au .
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