ORCID Profile
0000-0003-4522-1184
Current Organisation
University of Melbourne
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Publisher: The Endocrine Society
Date: 04-04-2019
Abstract: von Hippel-Lindau (VHL) disease, comprising renal cancer, hemangioblastoma, and/or pheochromocytoma (PHEO), is caused by missense or truncating variants of the VHL tumor-suppressor gene, which is involved in degradation of hypoxia-inducible factors (HIFs). However, the role of synonymous VHL variants in the disease is unclear. We evaluated a synonymous VHL variant in patients with familial PHEO or VHL disease without a detectable pathogenic VHL mutation. We performed genetic and transcriptional analyses of leukocytes and/or tumors from affected and unaffected in iduals and evaluated VHL splicing in existing cancer databases. We identified a synonymous VHL variant (c.414A G, p.Pro138Pro) as the driver event in five independent in iduals/families with PHEOs or VHL syndrome. This variant promotes exon 2 skipping and hence, abolishes expression of the full-length VHL transcript. Exon 2 spans the HIF-binding domain required for HIF degradation by VHL. Accordingly, PHEOs carrying this variant display HIF hyperactivation typical of VHL loss. Moreover, other exon 2 VHL variants from the The Cancer Genome Atlas pan-cancer datasets are biased toward expression of a VHL transcript that excludes this exon, supporting a broader impact of this spliced variant. A recurrent synonymous VHL variant (c.414A G, p.Pro138Pro) confers susceptibility to PHEO and VHL disease through splice disruption, leading to VHL dysfunction. This finding indicates that certain synonymous VHL variants may be clinically relevant and should be considered in genetic testing and surveillance settings. The observation that other coding VHL variants can exclude exon 2 suggests that dysregulated splicing may be an underappreciated mechanism in VHL-mediated tumorigenesis.
Publisher: Wiley
Date: 13-02-2023
DOI: 10.1002/PON.6104
Abstract: Patients with Cancer of Unknown Primary (CUP) commonly report poor understanding of their illness and high levels of psychological distress. Despite the potential benefits to CUP patients, there is a paucity of research exploring the reasons behind poor understanding of a CUP diagnosis. The aim of this study was to understand patients' experiences of communication with doctors, their understanding of diagnosis and the role of genomic testing, as well as their information needs. Semi‐structured interviews explored CUP patients' perceptions of communication with their doctors, understanding of their illness, and their needs regarding medical information. Qualitative inductive thematic analysis of transcribed audio‐recordings was employed. Nineteen patients were recruited from within a prospective cohort study involving routine genomic testing of CUP patients. CUP patients had varied perceptions of communication with doctors as well as different levels of need, readiness, and capacity for information. Some patients felt well understood and supported by their doctors while others did not. Many patients reported feeling overwhelmed and shocked when receiving their cancer diagnosis and emphasized the importance of family support in receiving and understanding medical information. While patients understood the implications of genomic testing for treatment and diagnosis, few had a detailed understanding of genomic testing. Patients' experience of communication and understanding of CUP could be potentially improved by clinicians' assessment of the communication style preferred by each patient and their family and the development of online resources to meet their evolving information needs.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9NJ03200B
Abstract: Pompom-like 3D hierarchical structured CoNi 2 S 4 nanofibers are obtained via a two-step anion exchange route, exhibiting good high-rate performance.
Publisher: Bioscientifica
Date: 2017
DOI: 10.1530/ERC-17-0306
Abstract: Pheochromocytomas (PC) and paragangliomas (PGL) are endocrine tumors for which the genetic and clinicopathological features of metastatic progression remain incompletely understood. As a result, the risk of metastasis from a primary tumor cannot be predicted. Early diagnosis of in iduals at high risk of developing metastases is clinically important and the identification of new biomarkers that are predictive of metastatic potential is of high value. Activation of TERT has been associated with a number of malignant tumors, including PC/PGL. However, the mechanism of TERT activation in the majority of PC/PGL remains unclear. As TERT promoter mutations occur rarely in PC/PGL, we hypothesized that other mechanisms – such as structural variations – may underlie TERT activation in these tumors. From 35 PC and four PGL, we identified three primary PCs that developed metastases with elevated TERT expression, each of which lacked TERT promoter mutations and promoter DNA methylation. Using whole genome sequencing, we identified somatic structural alterations proximal to the TERT locus in two of these tumors. In both tumors, the genomic rearrangements led to the positioning of super-enhancers proximal to the TERT promoter, that are likely responsible for the activation of the normally tightly repressed TERT expression in chromaffin cells
Publisher: MDPI AG
Date: 11-01-2021
DOI: 10.3390/DIAGNOSTICS11010103
Abstract: Blood-based liquid biopsies are considered a new and promising diagnostic and monitoring tool for cancer. As liquid biopsies only require a blood draw, they are non-invasive, potentially more rapid and assumed to be a less costly alternative to genomic analysis of tissue biopsies. A multi-disciplinary workshop (n = 98 registrations) was organized to discuss routine implementation of liquid biopsies in cancer management. Real-time polls were used to engage with experts’ about the current evidence of clinical utility and the barriers to implementation of liquid biopsies. Clinical, laboratory and health economics presentations were given to illustrate the opportunities and current levels of evidence, followed by three moderated break-out sessions to discuss applications. The workshop concluded that tumor-informed assays using next-generation sequencing (NGS) or PCR-based genotyping assays will most likely provide better clinical utility than tumor-agnostic assays, yet at a higher cost. For routine application, it will be essential to determine clinical utility, to define the minimum quality standards and performance of testing platforms and to ensure their use is integrated into current clinical workflows including how they complement tissue biopsies and imaging. Early health economic models may help identifying the most viable application of liquid biopsies. Alternative funding models for the translation of complex molecular diagnostics, such as liquid biopsies, may also be explored if clinical utility has been demonstrated and when their use is recommended in multi-disciplinary consensus guidelines.
Publisher: The Endocrine Society
Date: 03-2016
DOI: 10.1210/JC.2015-3889
Abstract: Pheochromocytomas and paragangliomas (PPGLs) are heritable neoplasms that can be classified into gene-expression subtypes corresponding to their underlying specific genetic drivers. This study aimed to develop a diagnostic and research tool (Pheo-type) capable of classifying PPGL tumors into gene-expression subtypes that could be used to guide and interpret genetic testing, determine surveillance programs, and aid in elucidation of PPGL biology. A compendium of published microarray data representing 205 PPGL tumors was used for the selection of subtype-specific genes that were then translated to the Nanostring gene-expression platform. A support vector machine was trained on the microarray dataset and then tested on an independent Nanostring dataset representing 38 familial and sporadic cases of PPGL of known genotype (RET, NF1, TMEM127, MAX, HRAS, VHL, and SDHx). Different classifier models involving between three and six subtypes were compared for their discrimination potential. A gene set of 46 genes and six endogenous controls was selected representing six known PPGL subtypes RTK1–3 (RET, NF1, TMEM127, and HRAS), MAX-like, VHL, and SDHx. Of 38 test cases, 34 (90%) were correctly predicted to six subtypes based on the known genotype to gene-expression subtype association. Removal of the RTK2 subtype from training, characterized by an admixture of tumor and normal adrenal cortex, improved the classification accuracy (35/38). Consolidation of RTK and pseudohypoxic PPGL subtypes to four- and then three-class architectures improved the classification accuracy for clinical application. The Pheo-type gene-expression assay is a reliable method for predicting PPGL genotype using routine diagnostic tumor s les.
Publisher: American Association for Cancer Research (AACR)
Date: 11-2008
DOI: 10.1158/1541-7786.MCR-08-0193
Abstract: Approximately, 10% to 15% of serous ovarian tumors fall into the category designated as tumors of low malignant potential (LMP). Like their invasive counterparts, LMP tumors may be associated with extraovarian disease, for ex le, in the peritoneal cavity and regional lymph nodes. However, unlike typical invasive carcinomas, patients generally have a favorable prognosis. The mutational profile also differs markedly from that seen in most serous carcinomas. Typically, LMP tumors are associated with KRAS and BRAF mutations. Interrogation of expression profiles in serous LMP tumors suggested overall redundancy of RAS-MAPK pathway mutations and a distinct mechanism of oncogenesis compared with high-grade ovarian carcinomas. Our findings indicate that activating mutation of the RAS-MAPK pathway in serous LMP may be present in & % of cases compared with ∼12.5% in serous ovarian carcinomas. In addition to mutations of KRAS (18%) and BRAF (48%) mutations, ERBB2 mutations (6%), but not EGFR, are prevalent among serous LMP tumors. Based on the expression profile signature observed throughout our serous LMP cohort, we propose that RAS-MAPK pathway activation is a requirement of serous LMP tumor development and that other activators of this pathway are yet to be defined. Importantly, as few nonsurgical options exist for treatment of recurrent LMP tumors, therapeutic targeting of this pathway may prove beneficial, especially in younger patients where maintaining fertility is important. (Mol Cancer Res 2008 (11):1678–90)
Publisher: BMJ
Date: 2023
Abstract: Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs. Patients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed. A total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB ( mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p .001). Among 110 CUPs with a latent primary or suspected TOO, 47% (52/110) belonged to ICI-responsive cancer types. More than half of the CUPs had at least one feature that may predict ICI response (high IR score, high TMB, ICI-responsive cancer type). Among patients with CUP treated with ICIs, 8/28 (29%) responded (2 complete responses and 6 partial responses). Among non-responders, 9 had stable and 11 had progressive disease. All responders had a high IR score (7/8) and/or high TMB (3/8), while most (5/8) belonged to ICI-responsive cancer types. These features were detected at a lower frequency in non-responders and mostly in patients with stable disease. A significant fraction of CUP tumors had genomic features previously associated with ICI response. High IR score was the most sensitive predictive feature of ICI response, warranting evaluation in a larger patient series.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 05-2015
DOI: 10.14694/EDBOOK_AM.2015.35.E519
Abstract: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous cancer that predominantly occurs in patients who are older, and is associated with a high rate of distant failure and mortality. Current management strategies that incorporate surgery and radiotherapy achieve high rates of locoregional control, but distant failure rates remain problematic, highlighting the need for new effective systemic therapies. Chemotherapy can achieve high response rates of limited duration in the metastatic setting, but its role in definitive management remains unproven. Recent developments in our knowledge about the biology of MCC have led to the identification of new potential therapeutic targets and treatments. A key finding has been the discovery that a human polyomavirus may be a causative agent. However, emerging data suggests that MCC may actually be two distinct entities, viral-associated and viral-negative MCC, which is likely to have implications for the management of MCC in the future and for the development of new treatments. In this review, we discuss recent discoveries about the biology of MCC, current approaches to management, and new therapeutic strategies that are being investigated.
Publisher: American Association for Cancer Research (AACR)
Date: 05-03-2021
DOI: 10.1158/2326-6066.CIR-20-0817
Abstract: Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4+ or CD8+ T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates (& % DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2− γδ T cells. In the context of γδ T–cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T–cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti–PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T–cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions. See related Spotlight on p. 600
Publisher: American Association for Cancer Research (AACR)
Date: 09-2016
DOI: 10.1158/1535-7163.MCT-15-0924
Abstract: Targeting BET bromodomain proteins using small molecules is an emerging anticancer strategy with clinical evaluation of at least six inhibitors now underway. Although MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional antitumor activities are important. Using the Eμ-Myc model of B-cell lymphoma, we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of proapoptotic (Bim) and antiapoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1 resistance phenotype. These studies provide important information on mechanisms of apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas. Mol Cancer Ther 15(9) 2030–41. ©2016 AACR.
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2011
Abstract: Emerging evidence suggests that poor glycemic control mediates post-translational modifications to the H3 histone tail. We are only beginning to understand the dynamic role of some of the erse epigenetic changes mediated by hyperglycemia at single loci, yet elevated glucose levels are thought to regulate genome-wide changes, and this still remains poorly understood. In this article we describe genome-wide histone H3K9/K14 hyperacetylation and DNA methylation maps conferred by hyperglycemia in primary human vascular cells. Chromatin immunoprecipitation (ChIP) as well as CpG methylation (CpG) assays, followed by massive parallel sequencing (ChIP-seq and CpG-seq) identified unique hyperacetylation and CpG methylation signatures with proximal and distal patterns of regionalization associative with gene expression. Ingenuity knowledge-based pathway and gene ontology analyses indicate that hyperglycemia significantly affects human vascular chromatin with the transcriptional up-regulation of genes involved in metabolic and cardiovascular disease. We have generated the first installment of a reference collection of hyperglycemia-induced chromatin modifications using robust and reproducible platforms that allow parallel sequencing-by-synthesis of immunopurified content. We uncover that hyperglycemia-mediated induction of genes and pathways associated with endothelial dysfunction occur through modulation of acetylated H3K9/K14 inversely correlated with methyl-CpG content.
Publisher: Wiley
Date: 12-11-2013
DOI: 10.1002/PATH.4251
Abstract: The clinical management of patients with cancer of unknown primary ( CUP ) is h ered by the absence of a definitive site of origin. We explored the utility of massively‐parallel (next‐generation) sequencing for the diagnosis of a primary site of origin and for the identification of novel treatment options. DNA enrichment by hybridization capture of 701 genes of clinical and/or biological importance, followed by massively‐parallel sequencing, was performed on 16 CUP patients who had defied attempts to identify a likely site of origin. We obtained high quality data from both fresh‐frozen and formalin‐fixed, paraffin‐embedded s les, demonstrating accessibility to routine diagnostic material. DNA copy‐number obtained by massively‐parallel sequencing was comparable to that obtained using oligonucleotide microarrays or quantitatively hybridized fluorescently tagged oligonucleotides. Sequencing to an average depth of 458‐fold enabled detection of somatically acquired single nucleotide mutations, insertions, deletions and copy‐number changes, and measurement of allelic frequency. Common cancer‐causing mutations were found in all cancers. Mutation profiling revealed therapeutic gene targets and pathways in 12/16 cases, providing novel treatment options. The presence of driver mutations that are enriched in certain known tumour types, together with mutational signatures indicative of exposure to sunlight or smoking, added to clinical, pathological, and molecular indicators of likely tissue of origin. Massively‐parallel DNA sequencing can therefore provide comprehensive mutation, DNA copy‐number, and mutational signature data that are of significant clinical value for a majority of CUP patients, providing both cumulative evidence for the diagnosis of primary site and options for future treatment. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-12-2019
Abstract: The ligands bound by γδ T cell receptors (TCRs) are less well characterized than those of their αβ TCR cousins, which are antigens presented by major histocompatibility complex (MHC) and related proteins. Le Nours et al. identified a phenotypically erse γδ T cell subset in human tissues that reacts to MHC-related protein 1 (MR1), which presents vitamin B derivatives. A crystal structure of a γδ TCR–MR1–antigen complex revealed that some of these TCRs can bind underneath the MR1 antigen-binding cleft instead of recognizing the presented antigen. This work thus uncovers an additional ligand for γδ T cells and reconceptualizes the nature of T cell antigen recognition. Science , this issue p. 1522
Publisher: Springer Science and Business Media LLC
Date: 06-03-2017
DOI: 10.1038/NCOMMS14581
Abstract: The Eμ- Myc mouse is an extensively used model of MYC driven malignancy however to date there has only been partial characterization of MYC co-operative mutations leading to spontaneous lymphomagenesis. Here we sequence spontaneously arising Eμ- Myc lymphomas to define transgene architecture, somatic mutations, and structural alterations. We identify frequent disruptive mutations in the PRC1-like component and BCL6-corepressor gene Bcor . Moreover, we find unexpected concomitant multigenic lesions involving Cdkn2a loss and other cancer genes including Nra s, Kras and Bcor . These findings challenge the assumed two-hit model of Eμ- Myc lymphoma and demonstrate a functional in vivo role for Bcor in suppressing tumorigenesis.
Publisher: Springer Science and Business Media LLC
Date: 30-11-2017
Publisher: Springer Science and Business Media LLC
Date: 04-04-2019
Publisher: American Chemical Society (ACS)
Date: 14-11-2022
DOI: 10.1021/ACSSENSORS.2C01460
Abstract: Improving outcomes for cancer patients during treatment and monitoring for cancer recurrence requires personalized care which can only be achieved through regular surveillance for biomarkers. Unfortunately, routine detection for blood-based biomarkers is cost-prohibitive using currently specialized laboratories. Using a rapid self-assembly sensing interface amenable to methods of mass production, we demonstrate the ability to detect and quantify a small carbohydrate-based cancer biomarker, Tn antigen (αGalNAc-Ser/Thr) in a small volume of blood, using a test format strip reminiscent of a blood glucose test. The detection of Tn antigen at picomolar levels is achieved through a new transduction mechanism based on the impact of Tn antigen interactions on the molecular dynamic motion of a lectin cross-linked lubricin antifouling brush. In tests performed on retrospective blood plasma s les from patients presenting three different tumor types, differentiation between healthy and diseased patients was achieved, highlighting the clinical potential for cancer monitoring.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2005
DOI: 10.1158/0008-5472.CAN-04-3617
Abstract: Gene expression profiling offers a promising new technique for the diagnosis and prognosis of cancer. We have applied this technology to build a clinically robust site of origin classifier with the ultimate aim of applying it to determine the origin of cancer of unknown primary (CUP). A single cDNA microarray platform was used to profile 229 primary and metastatic tumors representing 14 tumor types and multiple histologic subtypes. This data set was subsequently used for training and validation of a support vector machine (SVM) classifier, demonstrating 89% accuracy using a 13-class model. Further, we show the translation of a five-class classifier to a quantitative PCR–based platform. Selecting 79 optimal gene markers, we generated a quantitative-PCR low-density array, allowing the assay of both fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tissue. Data generated using both quantitative PCR and microarray were subsequently used to train and validate a cross-platform SVM model with high prediction accuracy. Finally, we applied our SVM classifiers to 13 cases of CUP. We show that the microarray SVM classifier was capable of making high confidence predictions in 11 of 13 cases. These predictions were supported by comprehensive review of the patients' clinical histories.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2014
DOI: 10.1158/2159-8290.CD-13-1042
Abstract: Summary: The future of cancer treatment lies in personalized strategies designed to specifically target tumorigenic cell populations present in an in idual. Although recent advances in directed therapies have greatly improved patient outcomes in some cancers, intuitive drug design is proving more difficult than expected owing largely to the complexity of human cancers. Intratumoral heterogeneity, the presence of multiple genotypically and/or phenotypically distinct cell subpopulations within a single tumor, is a likely cause of drug resistance. Advances in systems biology are helping to unravel the mysteries of cancer progression. In this issue of Cancer Discovery, Zhao and colleagues define a path for functional validation of computational modeling in the context of heterogeneous tumor populations and their potential for drug response and resistance. Cancer Discov 4(2) 146–8. ©2014 AACR. See related article by Zhao et al., p. 166
Publisher: Wiley
Date: 17-03-2015
DOI: 10.1038/ICB.2015.1
Abstract: The production and delivery of functional perforin (PRF PRF1 gene) by cytotoxic lymphocytes maintains immune homeostasis and tumour immune surveillance. In humans, inheritance of the common PRF1 polymorphism, p.A91V, (c.272C>T) found in 8-9% of the Caucasian population, with another mutated allele resulting in reduced PRF function or trafficking, has been shown to result in hyperinflammatory diseases and/or haematological cancers. In this study, we sought to investigate the function of p.A91V on a wild-type (WT) perforin background. We first developed an assay that distinguishes the relative levels of transcription of in idual PRF1 alleles, including p.A91V. The p.A91V allele was seen to be expressed at similar levels as the WT allele in primary human natural killer (NK) cells, ruling out that allelic expression imbalance influenced their function. We then demonstrated that the p.A91V mutation results in protein misfolding and an appreciable reduction in NK-cell cytotoxicity in healthy carriers of p.A91V. We propose that this level of cytotoxic dysfunction may readily account for the predisposition to immune-mediated disease in in iduals homozygous for p.A91V. Also, the fact that monoallelic mutations of PRF1 decrease NK-cell cytotoxicity should be considered in in iduals presenting with the manifestations of immune deficiency states that impinge on NK-cell cytotoxicity.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2023
Publisher: BMJ
Date: 10-2020
Abstract: Metastatic Merkel cell carcinoma (mMCC) is an aggressive neuroendocrine malignancy of the skin with a poor prognosis. Immune checkpoint inhibitors (ICIs) have shown substantial efficacy and favorable safety in clinical trials. Medical records of patients (pts) with mMCC treated with ICIs from August 2015 to December 2018 at Peter MacCallum Cancer Centre in Australia were analyzed. Response was assessed with serial imaging, the majority with FDG-PET/CT scans. RNA sequencing and immunohistochemistry for PD-L1, CD3 and Merkel cell polyomavirus (MCPyV) on tumor s les was performed. 23 pts with mMCC were treated with ICIs. A median of 8 cycles (range 1 to 47) were administered, with treatment ongoing in 6 pts. Objective responses (OR) were observed in 14 pts (61%): 10 (44%) complete responses (CR) and 4 (17%) partial responses (PR). Median time to response was 8 weeks (range 6 to 12) and 12-month progression-free survival rate was 39%. Increased OR were seen in pts aged less than 75 (OR 80% vs 46%), no prior history of chemotherapy (OR 64% vs 50%), patients with an immune-related adverse event (OR 100% vs 43%) and in MCPyV-negative tumors (OR 69% vs 43%). Pts with a CR had lower mean metabolic tumor volume on baseline FDG-PET/CT scan (CR: 35.7 mL, no CR: 187.8 mL, p=0.05). There was no correlation between PD-L1 positivity and MCPyV status (p=0.764) or OR (p=0.245). 10 pts received radiation therapy (RT) during ICI: 4 pts started RT concurrently (OR 75%, CR 50%), 3 pts had isolated ICI-resistant lesions successfully treated with RT and 3 pts with multisite progression continued to progress despite RT. Overall, 6 pts (26%) had grade 1–2 immune-related adverse events. ICIs showed efficacy and safety in mMCC consistent with trial data. Clinical and imaging predictors of response were identified.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2016
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2021
DOI: 10.1200/PO.21.00127
Publisher: Wiley
Date: 10-03-2016
DOI: 10.1002/IJC.30056
Abstract: Neuroblastoma is the most common extra-cranial malignancy in childhood and accounts for ∼15% of childhood cancer deaths. Amplification of MYCN in neuroblastoma is associated with aggressive disease and predicts for poor prognosis. Novel therapeutic approaches are therefore essential to improving patient outcomes in this setting. The histone deacetylases are known to interact with N-Myc and regulate numerous cellular processes via epigenetic modulation, including differentiation. In this study, we used the TH-MYCN mouse model of neuroblastoma to investigate the antitumor activity of the pan-HDAC inhibitor, panobinostat. In particular we sought to explore the impact of long term, continuous panobinostat exposure on the epigenetically driven differentiation process. Continuous treatment of tumor bearing TH-MYCN transgenic mice with panobinostat for nine weeks led to a significant improvement in survival as compared with mice treated with panobinostat for a three-week period. Panobinostat induced rapid tumor regression with no regrowth observed following a nine-week treatment period. Initial tumor response was associated with apoptosis mediated via upregulation of BMF and BIM. The process of terminal differentiation of neuroblastoma into benign ganglioneuroma, with a characteristic increase in S100 expression and reduction of N-Myc expression, occurred following prolonged exposure to the drug. RNA-sequencing analysis of tumors from treated animals confirmed significant upregulation of gene pathways associated with apoptosis and differentiation. Together our data demonstrate the potential of panobinostat as a novel therapeutic strategy for high-risk neuroblastoma patients.
Publisher: American Association for Cancer Research (AACR)
Date: 14-05-2014
DOI: 10.1158/1078-0432.CCR-13-3049
Abstract: Purpose: Gene-expression profiling has revolutionized the way we think about cancer and confers the ability to observe the synchronous expression of thousands of genes. The use of putative genome-level expression profiles has allowed biologists to observe the complex interactions of genes that constitute recognized biologic pathways. We used gastric and ovarian datasets to identify gene-expression signatures and determine any functional significance. Experimental Design: Microarray data of 94-tumor and 45-benign s les derived from patients with gastric cancer were interrogated using Hierarchical Ordered Partitioning and Collapsing Hybrid analysis identifying clusters of coexpressed genes. Clusters were further characterized with respect to biologic significance, gene ontology, and ability to discriminate between normal and tumor tissue. Tumor tissues were separated into epithelial and stromal compartments and immunohistochemical analysis performed to further elucidate specific cell lineages expressing genes contained in the signature. Results: We identified a “stromal-response” expression signature, highly enriched for inflammatory, extracellular matrix, cytokine, and growth factor proteins. The majority of genes in the signature are expressed in the tumor-associated stroma but were absent in associated premalignant conditions. In gastric cancer, this module almost perfectly differentiates tumor from nonmalignant gastric tissue and hence can be regarded as a highly tumor-specific gene-expression signature. Conclusions: We show that these genes are consistently coexpressed across a range of independent gastric datasets as well as other cancer types suggesting a conserved functional role in cancer. In addition, we show that this signature can be a surrogate marker for M2 macrophage activity and has significant prognostic implications in gastric and ovarian high-grade serous cancer. Clin Cancer Res 20(10) 2761–72. ©2014 AACR.
Publisher: Wiley
Date: 02-02-2015
DOI: 10.1002/PATH.4503
Publisher: Wiley
Date: 13-05-2017
DOI: 10.1002/PATH.4900
Abstract: Hereditary endocrine neoplasias, including phaeochromocytoma araganglioma and medullary thyroid cancer, are caused by autosomal dominant mutations in several familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours, or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion, but have undergone independent clonal evolution. Such tumours provide an opportunity to discover common cooperative changes required for tumourigenesis, while controlling for the genetic background of the in idual. We performed genomic analysis of synchronous and metachronous tumours from five patients bearing germline mutations in the genes SDHB, RET, and MAX. Using whole exome sequencing and high-density single-nucleotide polymorphism arrays, we analysed two to four primary tumours from each patient. We also applied multi-region s ling, to assess intratumoural heterogeneity and clonal evolution, in two cases involving paraganglioma and medullary thyroid cancer, respectively. Heterogeneous patterns of genomic change existed between synchronous or metachronous tumours, with evidence of branching evolution. We observed striking ex les of evolutionary convergence involving the same rare somatic copy-number events in synchronous primary phaeochromocytoma araganglioma. Convergent events also occurred during clonal evolution of metastatic medullary thyroid cancer. These observations suggest that genetic or epigenetic changes acquired early within precursor cells, or pre-existing within the genetic background of the in idual, create contingencies that determine the evolutionary trajectory of the tumour. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.JCIS.2019.01.011
Abstract: A three-dimensional (3D) graphene based photocatalyst, consisting of Fe(III)-doped NiAl layered double hydroxide (NiAlFe LDH), was prepared via a simple one-step hydrothermal approach for the first time. The growth of NiAlFe LDH nanoplates and the reduction of graphene oxide were accomplished simultaneously during hydrothermal process without adding toxic reductant and toxic solvent. No complex and time-consuming preparation steps were needed. The structural characterization shows that NiAlFe LDH nanoplates with a size of 100-150 nm vertically grow on the reduced graphene oxide (RGO) sheet, forming a unique 3D structured graphene based photocatalyst (NiAlFe LDH/RGO). The photocatalyst was applied for the first time to remove ciprofloxacin (CIP) in wastewater under visible-light illumination. Interestingly, after incorporating with an appropriate amount of Fe
Publisher: Springer Science and Business Media LLC
Date: 30-01-2017
Publisher: Elsevier BV
Date: 06-2020
Publisher: Springer Science and Business Media LLC
Date: 16-05-2012
DOI: 10.1038/NATURE11041
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.CELREP.2014.10.059
Abstract: Loss of heterozygosity (LOH) of the adenomatous polyposis coli (APC) gene triggers a series of molecular events leading to intestinal adenomagenesis. Haploinsufficiency of the cohesin Rad21 influences multiple initiating events in colorectal cancer (CRC). We identify Rad21 as a gatekeeper of LOH and a β-catenin target gene and provide evidence that Wnt pathway activation drives RAD21 expression in human CRC. Genome-wide analyses identified Rad21 as a key transcriptional regulator of critical CRC genes and long interspersed element (LINE-1 or L1) retrotransposons. Elevated RAD21 expression tracks with reactivation of L1 expression in human sporadic CRC, implicating cohesin-mediated L1 expression in global genomic instability and gene dysregulation in cancer.
Publisher: Public Library of Science (PLoS)
Date: 26-09-2013
Publisher: Wiley
Date: 03-07-2022
DOI: 10.1002/PON.5990
Abstract: Patients diagnosed with Cancer of Unknown Primary (CUP) experience high levels of psychological distress and report poor understanding of their cancer. We aimed to investigate: (1) if CUP patients with poorer understanding of their cancer diagnosis and testing experience more symptoms of psychological distress than those with better understanding (2) if the relationship between patients' understanding of their cancer and psychological distress is mediated by illness uncertainty and (3) explore whether patients' degree of understanding of their cancer can be predicted by clinical and socio‐demographic factors. 209 CUP patients completed a questionnaire measuring anxiety, depression, illness uncertainty, fatigue, pain, sleep and understanding of their cancer. Using an apriori theoretical framework, we employed structural equation modelling to investigate predictors of patient's understanding of their cancer and psychological distress and the relationships between understanding, illness uncertainty and distress. The structural equation model displayed good fit indices and supported the hypothesised relationship of patient's understanding of their cancer and the extent of psychological distress, which was mediated via illness uncertainty. Physical symptoms were positively associated with psychological distress and illness uncertainty. Younger age was predictive of lower patient's understanding of their cancer and higher levels of psychological distress. Patients with CUP, particularly those who are younger and experiencing more physical symptoms, report higher levels of psychological distress and may require additional mental health support. Our findings highlight a need to improve CUP patient's understanding about their illness, which could help reduce their illness uncertainty and alleviate psychological distress.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2022
DOI: 10.1007/S00520-022-07228-7
Abstract: This study aimed to determine the healthcare experiences, quality of life, and psychosocial needs of patients with cancer of unknown primary (CUP) early after diagnosis comparing their experiences to patients with advanced cancer of a known primary (non-CUP control patients) and published general population reference data where available. This study was a cross-sectional, multi-site study comparing CUP patients ( n = 139) compared to non-CUP controls ( n = 45). Demographic, clinical information and patient-reported outcome questionnaire data were collected at baseline. Differences in healthcare experienced were found between CUP and non-CUP controls with CUP patients reporting higher scores for unmet medical communication/information needs compared with non-CUP control patients ( p = 0.013) as well as greater uncertainty in illness ( p = 0.042). Whilst no differences were found between CUP and non-CUP controls on the EORTC and PROMIS measures, of those that ‘received written information about your cancer…’ and asked ‘…how useful was it?’ fewer CUP patients reported finding the information useful 40% vs 61%, and more were likely to not have received written information at all 59% vs 32% ( p = 0.002). Additionally, of those that found information about their cancer online, fewer patients with CUP reported finding it useful 32% vs 48% control patients ( p = 0.005). CUP patients have unmet medical communication/information needs and greater uncertainty in illness but do not differ in health-related quality of life domains compared to patients with advanced cancer of a known primary.
Publisher: Society of Nuclear Medicine
Date: 04-12-2020
Publisher: Elsevier BV
Date: 11-2020
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.
Publisher: Public Library of Science (PLoS)
Date: 15-01-2016
Publisher: BMJ
Date: 10-09-2018
DOI: 10.1136/JMEDGENET-2018-105427
Abstract: Until recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional to their penetrance for disease. We tested this hypothesis using data from two cohorts for succinate dehydrogenase subunits A, B and C ( SDHA–C ) genetic variants associated with hereditary pheochromocytoma araganglioma (PC/PGL). Two cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic SDHA–C variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas). Pathogenic SDHA–C variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 different pathogenic variants from both cohorts (seven in SDHA , 75 in SDHB and 12 in SDHC ), 13 are reported in ExAC (two in SDHA , nine in SDHB and two in SDHC ) accounting for 21% of subjects with SDHA–C variants. Combining data from both cohorts, estimated lifetime disease penetrance was 22.0% (95% CI 15.2% to 30.9%) for SDHB variants, 8.3% (95% CI 3.5% to 18.5%) for SDHC variants and 1.7% (95% CI 0.8% to 3.8%) for SDHA variants. Pathogenic variants in SDHB are more penetrant than those in SDHC and SDHA . Our findings have important implications for counselling and surveillance of subjects carrying these pathogenic variants.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2022
DOI: 10.1038/S41467-022-34011-3
Abstract: Pheochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors associated with autonomic nerves. Here we use single-nuclei RNA-seq and bulk-tissue gene-expression data to characterize the cellular composition of PCPG and normal adrenal tissues, refine tumor gene-expression subtypes and make clinical and genotypic associations. We confirm seven PCPG gene-expression subtypes with significant genotype and clinical associations. Tumors with mutations in VHL , SDH-encoding genes ( SDHx ) or MAML3 -fusions are characterized by hypoxia-inducible factor signaling and neoangiogenesis. PCPG have few infiltrating lymphocytes but abundant macrophages. While neoplastic cells transcriptionally resemble mature chromaffin cells, early chromaffin and neuroblast markers are also features of some PCPG subtypes. The gene-expression profile of metastatic SDHx -related PCPG indicates these tumors have elevated cellular proliferation and a lower number of non-neoplastic Schwann-cell-like cells, while GPR139 is a potential theranostic target. Our findings therefore clarify the erse transcriptional programs and cellular composition of PCPG and identify biomarkers of potential clinical significance.
Publisher: Oxford University Press (OUP)
Date: 02-01-2014
DOI: 10.1093/BIOINFORMATICS/BTT767
Abstract: Motivation: Methods for detecting somatic genome rearrangements in tumours using next-generation sequencing are vital in cancer genomics. Available algorithms use one or more sources of evidence, such as read depth, paired-end reads or split reads to predict structural variants. However, the problem remains challenging due to the significant computational burden and high false-positive or false-negative rates. Results: In this article, we present Socrates (SOft Clip re-alignment To idEntify Structural variants), a highly efficient and effective method for detecting genomic rearrangements in tumours that uses only split-read data. Socrates has single-nucleotide resolution, identifies micro-homologies and untemplated sequence at break points, has high sensitivity and high specificity and takes advantage of parallelism for efficient use of resources. We demonstrate using simulated and real data that Socrates performs well compared with a number of existing structural variant detection tools. Availability and implementation: Socrates is released as open source and available from bioinf.wehi.edu.au/socrates. Contact: papenfuss@wehi.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Wiley
Date: 05-08-2020
DOI: 10.1111/AJCO.13407
Publisher: Springer Science and Business Media LLC
Date: 13-12-2013
DOI: 10.1038/SREP03494
Publisher: Springer Science and Business Media LLC
Date: 20-02-2019
Publisher: Society of Nuclear Medicine
Date: 27-04-2017
Publisher: American Chemical Society (ACS)
Date: 09-03-2018
Publisher: Springer Science and Business Media LLC
Date: 18-10-2021
DOI: 10.1038/S41419-021-04141-5
Abstract: Anal cancer is a rare disease that has doubled in incidence over the last four decades. Current treatment and survival of patients with this disease has not changed substantially over this period of time, due, in part, to a paucity of preclinical models to assess new therapeutic options. To address this hiatus, we set-out to establish, validate and characterise a panel of human anal squamous cell carcinoma (ASCC) cell lines by employing an explant technique using fresh human ASCC tumour tissue. The panel of five human ASCC cell lines were validated to confirm their origin, squamous features and tumourigenicity, followed by molecular and genomic (whole-exome sequencing) characterisation. This panel recapitulates the genetic and molecular characteristics previously described in ASCC including phosphoinositide-3-kinase (PI3K) mutations in three of the human papillomavirus (HPV) positive lines and TP53 mutations in the HPV negative line. The cell lines demonstrate the ability to form tumouroids and retain their tumourigenic potential upon xenotransplantation, with varied inducible expression of major histocompatibility complex class I (MHC class I) and Programmed cell death ligand 1 (PD-L1). We observed differential responses to standard chemotherapy, radiotherapy and a PI3K specific molecular targeted agent in vitro, which correlated with the clinical response of the patient tumours from which they were derived. We anticipate this novel panel of human ASCC cell lines will form a valuable resource for future studies into the biology and therapeutics of this rare disease.
Publisher: Public Library of Science (PLoS)
Date: 23-11-2020
DOI: 10.1371/JOURNAL.PONE.0241437
Abstract: In Bangladesh, about 80% of healthcare is provided by the private sector. Although free diagnosis and care is offered in the public sector, only half of the estimated number of people with tuberculosis are diagnosed, treated, and notified to the national program. Private sector engagement strategies often have been small scale and time limited. We evaluated a Social Enterprise Model combining external funding and income generation at three tuberculosis screening centres across the Dhaka Metropolitan Area for diagnosing and treating tuberculosis. The model established three tuberculosis screening centres across Dhaka Metropolitan Area that carried the icddr,b brand and offered free Xpert MTB/RIF tests to patients visiting the screening centres for subsidized, digital chest radiographs from April 2014 to December 2017. A network of private and public health care providers, and community recommendation was formed for patient referral. No financial incentives were offered to physicians for referrals. Revenues from radiography were used to support screening centres’ operation. Tuberculosis patients could choose to receive treatment from the private or public sector. Between 2014 and 2017, 1,032 private facilities networked with 8,466 private providers were mapped within the Dhaka Metropolitan Area. 64, 031 patients with TB symptoms were referred by the private providers, public sector and community residents to the three screening centres with 80% coming from private providers. 4,270 private providers made at least one referral. Overall, 10,288 pulmonary and extra-pulmonary tuberculosis cases were detected and 7,695 were bacteriologically positive by Xpert, corresponding to 28% of the total notifications in Dhaka Metropolitan Area. The model established a network of private providers who referred in iduals with presumptive tuberculosis without financial incentives to icddr,b’s screening centres, facilitating a quarter of total tuberculosis notifications in Dhaka Metropolitan Area. Scaling up this approach may enhance national and international tuberculosis response.
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2009
DOI: 10.1158/1078-0432.CCR-08-1564
Abstract: Purpose: A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-based treatment. We analyzed somatic DNA copy number variation and gene expression data to identify key mechanisms associated with primary resistance in advanced-stage serous cancers. Experimental Design: Genome-wide copy number variation was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays. A well-defined subset of 85 advanced-stage serous tumors was then used to relate copy number variation to primary resistance to treatment. The discovery-based approach was complemented by quantitative-PCR copy number analysis of 12 candidate genes as independent validation of previously reported associations with clinical outcome. Likely copy number variation targets and tumor molecular subtypes were further characterized by gene expression profiling. Results: Amplification of 19q12, containing cyclin E (CCNE1), and 20q11.22-q13.12, mapping immediately adjacent to the steroid receptor coactivator NCOA3, was significantly associated with poor response to primary treatment. Other genes previously associated with copy number variation and clinical outcome in ovarian cancer were not associated with primary treatment resistance. Chemoresistant tumors with high CCNE1 copy number and protein expression were associated with increased cellular proliferation but so too was a subset of treatment-responsive patients, suggesting a cell-cycle independent role for CCNE1 in modulating chemoresponse. Patients with a poor clinical outcome without CCNE1 lification overexpressed genes involved in extracellular matrix deposition. Conclusions: We have identified two distinct mechanisms of primary treatment failure in serous ovarian cancer, involving CCNE1 lification and enhanced extracellular matrix deposition. CCNE1 copy number is validated as a dominant marker of patient outcome in ovarian cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2018
DOI: 10.1158/1078-0432.CCR-18-1184
Abstract: Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. There is an unmet need for MCC-specific blood-based surrogate biomarkers of tumor burden circulating cell-free miRNA may serve this purpose. Expression of miR-375 was quantified in 24 MCC and 23 non-MCC cell lines, 67 MCC and 58 non-MCC tumor tissues, sera of 2 preclinical MCC models, and sera of 109 patients with MCC and 30 healthy controls by nCounter human-v2-miRNA expression or miR-375–specific real-time PCR assays. The patients’ sera consisted of two retrospective (discovery and training) and two prospective (validation) cohorts. miR-375 expression was high in MCC cell lines and tissues compared with non-MCCs. It was readily detected in MCC-conditioned medium and sera of preclinical models bearing MCC xenografts. miR-375 levels were higher in sera from tumor-bearing patients with MCC than in tumor-free patients or healthy controls (P & 0.0005). Moreover, miR-375 serum levels correlated with tumor stage in tumor-bearing (P = 0.037) but not in tumor-free (P = 0.372) patients with MCC. miR-375 serum level showed high diagnostic accuracy to discriminate tumor-bearing and tumor-free patients with MCC as demonstrated by ROC curve analysis in the retrospective cohorts (AUC = 0.954 and 0.800) as well as in the prospective cohorts (AUC = 0.929 and 0.959). miR-375 serum level reflected dynamic changes in tumor burden of patients with MCC during therapeutic interventions. Circulating cell-free miR-375 proved as a surrogate marker for tumor burden in MCC without restriction to polyomavirus positivity it thus appears to be useful for therapy monitoring and the follow-up of patients with MCC.
Publisher: Bioscientifica
Date: 10-2020
DOI: 10.1530/ERC-19-0474E
Publisher: Springer Science and Business Media LLC
Date: 12-2002
DOI: 10.1038/NG1030
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.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2020
Publisher: Bioscientifica
Date: 06-2020
DOI: 10.1530/ERC-19-0474
Abstract: Tumors caused by loss-of-function mutations in genes encoding TCA cycle enzymes have been recently discovered and are now of great interest. Mutations in succinate dehydrogenase (SDH) subunits cause pheochromocytoma araganglioma (PCPG) and syndromically associated tumors, which differ phenotypically and clinically from more common SDH-intact tumors of the same types. Consequences of SDH deficiency include rewired metabolism, pseudohypoxic signaling and altered redox balance. PCPG with SDHB mutations are particularly aggressive, and development of treatments has been h ered by lack of valid experimental models. Attempts to develop mouse models have been unsuccessful. Using a new strategy, we developed a xenograft and cell line model of SDH-deficient pheochromocytoma from rats with a heterozygous germline Sdhb mutation. The genome, transcriptome and metabolome of this model, called RS0, closely resemble those of SDHB -mutated human PCPGs, making it the most valid model now available. Strategies employed to develop RS0 may be broadly applicable to other SDH-deficient tumors.
Publisher: Elsevier BV
Date: 10-2019
Publisher: American Association for Cancer Research (AACR)
Date: 12-08-2008
DOI: 10.1158/1078-0432.CCR-08-0196
Abstract: Purpose: The study aim to identify novel molecular subtypes of ovarian cancer by gene expression profiling with linkage to clinical and pathologic features. Experimental Design: Microarray gene expression profiling was done on 285 serous and endometrioid tumors of the ovary, peritoneum, and fallopian tube. K-means clustering was applied to identify robust molecular subtypes. Statistical analysis identified differentially expressed genes, pathways, and gene ontologies. Laser capture microdissection, pathology review, and immunohistochemistry validated the array-based findings. Patient survival within k-means groups was evaluated using Cox proportional hazards models. Class prediction validated k-means groups in an independent dataset. A semisupervised survival analysis of the array data was used to compare against unsupervised clustering results. Results: Optimal clustering of array data identified six molecular subtypes. Two subtypes represented predominantly serous low malignant potential and low-grade endometrioid subtypes, respectively. The remaining four subtypes represented higher grade and advanced stage cancers of serous and endometrioid morphology. A novel subtype of high-grade serous cancers reflected a mesenchymal cell type, characterized by overexpression of N-cadherin and P-cadherin and low expression of differentiation markers, including CA125 and MUC1. A poor prognosis subtype was defined by a reactive stroma gene expression signature, correlating with extensive desmoplasia in such s les. A similar poor prognosis signature could be found using a semisupervised analysis. Each subtype displayed distinct levels and patterns of immune cell infiltration. Class prediction identified similar subtypes in an independent ovarian dataset with similar prognostic trends. Conclusion: Gene expression profiling identified molecular subtypes of ovarian cancer of biological and clinical importance.
Publisher: Wiley
Date: 30-11-2022
DOI: 10.1002/PATH.6022
Abstract: Cancer of unknown primary (CUP) is a syndrome defined by clinical absence of a primary cancer after standardised investigations. Gene expression profiling (GEP) and DNA sequencing have been used to predict primary tissue of origin (TOO) in CUP and find molecularly guided treatments however, a detailed comparison of the diagnostic yield from these two tests has not been described. Here, we compared the diagnostic utility of RNA and DNA tests in 215 CUP patients (82% received both tests) in a prospective Australian study. Based on retrospective assessment of clinicopathological data, 77% (166/215) of CUPs had insufficient evidence to support TOO diagnosis (clinicopathology unresolved). The remainder had either a latent primary diagnosis (10%) or clinicopathological evidence to support a likely TOO diagnosis (13%) (clinicopathology resolved). We applied a microarray (CUPGuide) or custom NanoString 18‐class GEP test to 191 CUPs with an accuracy of 91.5% in known metastatic cancers for high–medium confidence predictions. Classification performance was similar in clinicopathology‐resolved CUPs – 80% had high–medium predictions and 94% were concordant with pathology. Notably, only 56% of the clinicopathology‐unresolved CUPs had high–medium confidence GEP predictions. Diagnostic DNA features were interrogated in 201 CUP tumours guided by the cancer type specificity of mutations observed across 22 cancer types from the AACR Project GENIE database (77,058 tumours) as well as mutational signatures (e.g. smoking). Among the clinicopathology‐unresolved CUPs, mutations and mutational signatures provided additional diagnostic evidence in 31% of cases. GEP classification was useful in only 13% of cases and oncoviral detection in 4%. Among CUPs where genomics informed TOO, lung and biliary cancers were the most frequently identified types, while kidney tumours were another identifiable subset. In conclusion, DNA and RNA profiling supported an unconfirmed TOO diagnosis in one‐third of CUPs otherwise unresolved by clinicopathology assessment alone. DNA mutation profiling was the more diagnostically informative assay. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.YGYNO.2016.06.023
Abstract: Primary peritoneal cancer is rare and considered equivalent to stage III/IV ovarian cancer, but questions remain concerning its underlying biology, prognosis and optimal management. Clinico-pathological and treatment details of primary peritoneal (n=120) and ovarian cancer (n=635) were obtained on women recruited to the Australian Ovarian Cancer Study. Log-rank test was used to compare survival and cox proportional hazards models were fitted to obtain hazard ratios and 95% confidence intervals, both unadjusted and adjusted for age, grade, FIGO stage, residual disease and treatment with neoadjuvant chemotherapy. Molecular subtype was determined by gene expression profiling using published data. Compared with advanced serous ovarian cancer, primary peritoneal cancer patients were older (mean age 65.5 vs. 60.2years, p<0.001), more often treated with neoadjuvant chemotherapy (38.4% vs. 11.4%, p<0.001). Gene expression profiling classified a substantially higher proportion of primary peritoneal carcinomas as C1 (mesenchymal, reactive stromal infiltration) subtype (70.6% vs. 32.1%, p=0.029), which was associated with lower complete surgical resection rate. Women with primary peritoneal cancer had significantly shorter progression-free (11.6 vs. 13.6months, p=0.007) and overall survival (31.7 vs. 39.8months, p=0.012). In multivariate analysis, residual disease and neoadjuvant chemotherapy were both independently associated with increased risk of progression and death. Primary peritoneal cancer patients were more frequently treated with neoadjuvant chemotherapy and had inferior survival. Different tumor biology characterized by activated stromal fibrosis in primary peritoneal cancer may underlie the differences in treatment and clinical outcome.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2015
DOI: 10.1038/NATURE14410
Abstract: Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA s les from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 lification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in in idual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.
Publisher: Cold Spring Harbor Laboratory
Date: 21-04-2023
DOI: 10.1101/2023.04.20.537744
Abstract: Metazoans inherited genes from unicellular ancestors that perform essential biological processes such as cell ision, metabolism and protein translation. Functioning multicellularity requires careful control and coordination of these unicellular genes to maintain tissue integrity and homeostasis. Gene regulatory networks (GRNs) formed during metazoan evolution to regulate conserved biological processes are frequently altered in cancer, resulting in over-expression of unicellular genes. We propose an imbalance in co-expression of unicellular (UC) and multicellular (MC) genes is a driving force in cancer. To investigate, we combined gene co-expression analysis to infer changes to GRNs in cancer with protein sequence conservation data to distinguish genes with UC and MC origins. Co-expression networks created using RNA sequencing data from 31 tumour types and normal tissue s les were ided into modules enriched for UC genes, MC genes or a mix of both (Mixed UC-MC modules). The greatest differences between tumour and normal tissue co-expression networks occurred within Mixed UC-MC modules. In particular, MC and UC genes not commonly co-expressed in normal tissues formed distinct co-expression modules seen only in tumours. The degree of rewiring of genes within Mixed UC-MC modules increased with both tumour grade and stage. Mixed UC-MC modules were enriched for somatic mutations in cancer genes, particularly copy-number lifications, suggesting an important driver of the rewiring observed in tumours are copy-number changes. Overall, our study shows the greatest changes to gene co-expression patterns during tumour progression occur between genes of MC and UC origins, implicating the breakdown and rewiring of metazoan gene regulatory networks in cancer development and progression. Multicellular organism cells follow certain rules that control and coordinate their growth and behavior. This happens because gene regulatory networks formed during the evolution of multicellularity to control the activity of genes inherited from unicellular ancestors. Cancer cells disobey these rules, growing and iding in a competitive fashion analogous to that of colonial unicellular organisms. Here, we test the hypothesis that breakdown of gene regulatory networks enforcing multicellularity drives cancer progression by investigating 31 tumour types. Based on sequence similarity, genes were categorized as having origins in either unicellular or multicellular species. We found that the balance of expression unicellular and multicellular genes changes dramatically in cancer. Genes expressed together in normal tissues stop being co-expressed in tumors, while unicellular and multicellular genes that would not normally be expressed together in normal tissues become highly co-expressed. This phenomenon is more pronounced in cancers at more advanced stages, and sometimes occurs in association with gain or loss of parts of certain chromosomes. Our work indicates disruption and rewiring of gene regulatory networks that evolved to enforce multicellularity drives cancer progression by upsetting the carefully coordinated balance in the activity of unicellular and multicellular genes.
Publisher: American Society for Clinical Investigation
Date: 02-04-2019
DOI: 10.1172/JCI123089
Publisher: Oxford University Press (OUP)
Date: 02-04-2012
DOI: 10.1093/BIOINFORMATICS/BTS146
Abstract: Motivation: In light of the increasing adoption of targeted resequencing (TR) as a cost-effective strategy to identify disease-causing variants, a robust method for copy number variation (CNV) analysis is needed to maximize the value of this promising technology. Results: We present a method for CNV detection for TR data, including whole-exome capture data. Our method calls copy number gains and losses for each target region based on normalized depth of coverage. Our key strategies include the use of base-level log-ratios to remove GC-content bias, correction for an imbalanced library size effect on log-ratios, and the estimation of log-ratio variations via binning and interpolation. Our methods are made available via CONTRA (COpy Number Targeted Resequencing Analysis), a software package that takes standard alignment formats (BAM/SAM) and outputs in variant call format (VCF4.0), for easy integration with other next-generation sequencing analysis packages. We assessed our methods using s les from seven different target enrichment assays, and evaluated our results using simulated data and real germline data with known CNV genotypes. Availability and implementation: Source code and s le data are freely available under GNU license (GPLv3) at contra-cnv.sourceforge.net/ Contact: Jason.Li@petermac.org Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Elsevier BV
Date: 04-2019
Publisher: Elsevier BV
Date: 2015
Publisher: Springer Science and Business Media LLC
Date: 23-06-2020
DOI: 10.1038/S41598-020-67199-9
Abstract: Peptide receptor radionuclide therapy (PRRT) is an important treatment option for patients with somatostatin receptor-2 (SSTR2)-expressing neuroendocrine tumour (NET) though tumour regression occurs in only a minority of patients. Therefore, novel PRRT regimens with improved therapeutic activity are needed. Radiation induced DNA damage repair is an attractive therapeutic target to increase PRRT efficacy and consequently, we have characterised a panel of preclinical models for their SSTR2 expression, in vivo growth properties and response to 177 Lu-DOTA-octreotate (LuTate) PRRT to identify models with features suitable for evaluating novel therapeutic combinations . In vitro studies using the SSTR2 expressing AR42J model demonstrate that the combination of LuTate and the small molecule Poly(ADP-ribose) polymerase-1 (PARP) inhibitor, talazoparib led to increased DNA double strand breaks, as assessed by γ-H2AX foci formation, as compared to LuTate alone. Furthermore, using the AR42J tumour model in vivo we demonstrate that the combination of LuTate and talazoparib significantly improved the anti-tumour efficacy of LuTate alone. These findings support the clinical evaluation of the combination of LuTate and PARP inhibition in SSTR2-expressing NET.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2023
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Richard William Tothill.