ORCID Profile
0000-0001-5078-6687
Current Organisations
Garvan Institute of Medical Research
,
Children's Cancer Institute Australia
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Publisher: Springer Science and Business Media LLC
Date: 27-03-2017
DOI: 10.1038/ONC.2017.63
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2008
Publisher: Cold Spring Harbor Laboratory
Date: 04-2019
DOI: 10.1101/MCS.A003764
Abstract: Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 years using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2 , TP53 , RB1 , and PTEN , resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses.
Publisher: Public Library of Science (PLoS)
Date: 28-04-2009
Publisher: Elsevier BV
Date: 06-1993
Publisher: Springer Science and Business Media LLC
Date: 21-11-2014
DOI: 10.1038/BJC.2013.722
Publisher: Springer Science and Business Media LLC
Date: 28-09-2016
Publisher: Springer Science and Business Media LLC
Date: 24-02-2016
DOI: 10.1038/NATURE16965
Abstract: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous (2) pancreatic progenitor (3) immunogenic and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2017
DOI: 10.1038/NATURE21063
Abstract: The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
Publisher: Public Library of Science (PLoS)
Date: 20-08-2008
Publisher: American Association for Cancer Research (AACR)
Date: 14-11-2010
DOI: 10.1158/0008-5472.CAN-10-0911
Abstract: To identify therapeutic targets and prognostic markers for basal breast cancers, breast cancer cell lines were subjected to mass spectrometry–based profiling of protein tyrosine phosphorylation events. This revealed that luminal and basal breast cancer cells exhibit distinct tyrosine phosphorylation signatures that depend on pathway activation as well as protein expression. Basal breast cancer cells are characterized by elevated tyrosine phosphorylation of Met, Lyn, EphA2, epidermal growth factor receptor (EGFR), and FAK, and Src family kinase (SFK) substrates such as p130Cas. SFKs exert a prominent role in these cells, phosphorylating key regulators of adhesion and migration and promoting tyrosine phosphorylation of the receptor tyrosine kinases EGFR and Met. Consistent with these observations, SFK inhibition attenuated cellular proliferation, survival, and motility. Basal breast cancer cell lines exhibited differential responsiveness to small molecule inhibitors of EGFR and Met that correlated with the degree of target phosphorylation, and reflecting kinase coactivation, inhibiting two types of activated network kinase (e.g., EGFR and SFKs) was more effective than single agent approaches. FAK signaling enhanced both proliferation and invasion, and Lyn was identified as a proinvasive component of the network that is associated with a basal phenotype and poor prognosis in patients with breast cancer. These studies highlight multiple kinases and substrates for further evaluation as therapeutic targets and biomarkers. However, they also indicate that patient stratification based on expression/activation of drug targets, coupled with use of multi-kinase inhibitors or combination therapies, may be required for effective treatment of this breast cancer subgroup. Cancer Res 70(22) 9391–401. ©2010 AACR.
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1053/J.GASTRO.2009.04.009
Abstract: Current methods of preoperative staging and predicting outcome following pancreatectomy for pancreatic cancer (PC) are inadequate. We evaluated the utility of multiple biomarkers from distinct biologic pathways as potential predictive markers of response to pancreatectomy and patient survival. We assessed the relationship of candidate biomarkers known, or suspected, to be aberrantly expressed in PC, with disease-specific survival and response to therapy in a cohort of 601 patients. Of the 17 candidate biomarkers examined, only elevated expression of S100A2 was an independent predictor of survival in both the training (n = 162) and validation sets (n = 439 hazard ratio [HR], 2.19 95% confidence interval [CI]: 1.48-3.25 P < .0001) when assessed in a multivariate model with clinical variables. Patients with high S100A2 expressing tumors had no survival benefit with pancreatectomy compared with those with locally advanced disease, whereas those without high S100A2 expression had a survival advantage of 10.6 months (19.4 vs 8.8 months, respectively) and a HR of 3.23 (95% CI: 2.39-4.33 P < .0001). Of significance, patients with S100A2-negative tumors had a significant survival benefit from pancreatectomy even in the presence of involved surgical margins (median, 15.7 months P = .0007) or lymph node metastases (median, 17.4 months P = .0002). S100A2 expression is a good predictor of response to pancreatectomy for PC and suggests that high S100A2 expression may be a marker of a metastatic phenotype. Prospective measurement of S100A2 expression in diagnostic biopsy s les has potential clinical utility as a predictive marker of response to pancreatectomy and other therapies that target locoregional disease.
Publisher: Oxford University Press (OUP)
Date: 08-11-2011
DOI: 10.1093/NAR/GKR967
Publisher: Wiley
Date: 10-2007
Abstract: The natural polyphenol resveratrol stimulates sirtuins and extends lifespan. Here resveratrol inhibited expression of replicative senescence marker INK4a in human dermal fibroblasts, and 47 of 19,000 genes from microarray experiments were differentially expressed. These included genes for growth, cell ision, cell signaling, apoptosis, and transcription. Genes involved in Ras and ubiquitin pathways, Ras-GRF1, RAC3, and UBE2D3, were downregulated. The changes suggest resveratrol might alter sirtuin-regulated downstream pathways, rather than sirtuin activity. Serum deprivation and high confluency caused nuclear translocation of the SIRT1-regulated transcription factor FOXO3a. Our data indicate resveratrol's actions might cause FOXO recruitment to the nucleus.
Publisher: Wiley
Date: 14-10-2014
DOI: 10.1002/CNCR.28863
Abstract: Inherited predisposition to pancreatic cancer contributes significantly to its incidence and presents an opportunity for the development of early detection strategies. The genetic basis of predisposition remains unexplained in a high proportion of patients with familial PC (FPC). Clinicopathologic features were assessed in a cohort of 766 patients who had been diagnosed with pancreatic ductal adenocarcinoma (PC). Patients were classified with FPC if they had ≥1 affected first-degree relatives otherwise, they were classified with sporadic PC (SPC). The prevalence of FPC in this cohort was 8.9%. In FPC families with an affected parent-child pair, 71% in the subsequent generation were 12.3 years younger at diagnosis. Patients with FPC had more first-degree relatives who had an extrapancreatic malignancy (EPM) (42.6% vs 21.2 P 2 years) was associated with poor survival in both groups. FPC represents 9% of PC, and the risk of malignancy in kindred does not appear to be confined to the pancreas. Patients with FPC have more precursor lesions and include fewer active smokers, but other clinicopathologic factors and outcome are similar to those in patients with SPC. Furthermore, some FPC kindreds may exhibit anticipation. A better understanding of the clinical features of PC will facilitate efforts to uncover novel susceptibility genes and the development of early detection strategies.
Publisher: Public Library of Science (PLoS)
Date: 25-09-2012
Publisher: Springer Science and Business Media LLC
Date: 07-03-2011
DOI: 10.1038/ONC.2011.36
Abstract: Recognition of the pivotal role of estrogen in the aetiology of breast cancer has led to the development of antiestrogens (AE), such as tamoxifen (TAM) as effective therapies for the treatment and prevention of this disease. However, despite their widespread clinical efficacy, response to AEs is often short-lived, and acquired or innate therapeutic resistance remains a major obstacle in the successful treatment of breast cancer. Thus, delineating the intracellular pathways that mediate the cellular response to estrogen could potentially lead to new, more effective approaches to the treatment of breast cancer, particularly endocrine-resistant disease. Here, we have identified the BCL-2 homology 3 (BH3)-only, pro-apoptotic regulator, PUMA (p53 upregulated modulator of apoptosis) as an estrogen target gene that is acutely downregulated in response to estrogen in breast cancer cell lines, independently of their p53 status. PUMA is transcriptionally upregulated following treatment with TAM, and knock down of PUMA expression in these cells attenuates the apoptotic response to TAM. Furthermore, low PUMA expression in breast carcinomas is significantly associated with breast cancer-specific death (P=0.0014 and P=0.0115, for mRNA and protein, respectively), and worse outcome in TAM-treated patients (mRNA, P=1.49e-05). These findings suggest that the dysregulation of apoptotic signaling pathways such as those executed through PUMA, can significantly impact on both the progression and therapeutic responsiveness of breast cancer. Moreover, they provide a convincing rationale for exploring new therapeutic approaches involving endocrine and non-endocrine therapies that target apoptotic pathways as an effective strategy for tackling endocrine refractory disease.
Publisher: Elsevier BV
Date: 2009
Publisher: Cold Spring Harbor Laboratory
Date: 18-11-2018
DOI: 10.1101/473348
Abstract: Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly in iduals. Here we describe the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2,570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analysed the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. In iduals in the MGRB had fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK BioBank cohorts, consistent with risk depletion. Pervasive age-related somatic changes were correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing. This research has been conducted using the UK Biobank Resource under Application Number 17984.
Publisher: Springer Science and Business Media LLC
Date: 25-02-2015
DOI: 10.1038/NATURE14169
Publisher: Springer Science and Business Media LLC
Date: 24-10-2019
Publisher: Spandidos Publications
Date: 16-02-2015
Abstract: Despite incremental advances in the diagnosis and treatment for pancreatic cancer (PC), the 5‑year survival rate remains <5%. Novel therapies to increase survival and quality of life for PC patients are desperately needed. Epigenetic thera-peutic agents such as histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have demonstrated therapeutic benefits in human cancer. We assessed the efficacy of these epigenetic therapeutic agents as potential therapies for PC using in vitro and in vivo models. Treatment with HDACi [suberoylanilide hydroxamic acid (SAHA)] and DNMTi [5‑AZA‑2' deoxycytidine (5‑AZA‑dc)] decreased cell proliferation in MiaPaCa2 cells, and SAHA treatment, with or without 5‑AZA‑dc, resulted in higher cell death and lower DNA synthesis compared to 5‑AZA‑dc alone and controls (DMSO). Further, combination treatment with SAHA and 5‑AZA‑dc significantly increased expression of p21WAF1, leading to G1 arrest. Treatment with epigenetic agents delayed tumour growth in vivo, but did not decrease growth of established pancreatic tumours. In conclusion, these data demonstrate a potential role for epigenetic modifier drugs for the management of PC, specifically in the chemoprevention of PC, in combination with other chemotherapeutic agents.
Publisher: EMBO
Date: 15-06-2015
Publisher: Elsevier BV
Date: 07-2008
Publisher: Springer Science and Business Media LLC
Date: 09-12-2008
Publisher: Elsevier BV
Date: 2017
DOI: 10.1053/J.GASTRO.2016.09.060
Abstract: Pancreatic cancer is molecularly erse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in in idual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2012
DOI: 10.1038/NATURE11547
Publisher: Cold Spring Harbor Laboratory
Date: 03-11-2020
DOI: 10.1101/MCS.A005710
Abstract: The identification of rearrangements driving expression of neurotrophic receptor tyrosine kinase ( NTRK ) family kinases in tumors has become critically important because of the availability of effective, specific inhibitor drugs. Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) can identify novel and recurrent expressed fusions. Here we describe three SPECC1L–NTRK fusions identified in two pediatric central nervous system cancers and an extracranial solid tumor using WGS and RNA-seq. These fusions arose either through a simple balanced rearrangement or in the context of a complex chromoplexy event. We cloned the SPECC1L–NTRK2 fusion directly from a patient s le and showed that enforced expression of this fusion is sufficient to promote cytokine-independent survival and proliferation. Cells transformed by SPECC1L–NTRK2 expression are sensitive to a TRK inhibitor drug. We report here that SPECC1L–NTRK fusions can arise in a range of pediatric cancers. Although WGS and RNA-seq are not required to detect NTRK fusions, these techniques may be of benefit when NTRK fusions are not suspected on clinical grounds or not identified by other methods.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2013
Abstract: In iduals with adenocarcinoma of the ulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ulla of Vater. Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34 95% CI, 1.69 to 6.62 P .001) and both validation cohorts (HR, 5.65 95% CI, 2.77 to 11.5 P .001 and HR, 2.78 95% CI, 1.25 to 7.17 P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.
Publisher: Cold Spring Harbor Laboratory
Date: 08-10-2018
DOI: 10.1101/432872
Abstract: The grouping of cancers across tissue boundaries is central to precision oncology, but remains a difficult problem. Here we present EPICC (Experimental Protein Interaction Clustering of Cancer), a novel technique to cluster cancer patients based on DNA mutation profile, that leverages knowledge of protein-protein interactions to reduce noise and lify biological signal. We applied EPICC to data from The Cancer Genome Atlas (TCGA), and both recapitulated known cancer clusterings, and identified new cross-tissue cancer groups that may indicate novel cancer molecular subtypes. Investigation of EPICC clusters revealed new protein modules which were recurrently mutated across cancers, and indicate new avenues for research into cancer biology. EPICC leveraged the Vodafone DreamLab citizen science platform, and we provide our results as a resource for researchers to investigate the role of protein modules in cancer.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2020
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-04-2017
DOI: 10.1126/SCITRANSLMED.AAI8504
Abstract: Fine-tuned manipulation of tumor tension and vasculature enhances response to chemotherapy and impairs metastatic spread in pancreatic cancer.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2008
Publisher: Springer Science and Business Media LLC
Date: 09-09-2014
Publisher: Springer Science and Business Media LLC
Date: 17-04-2019
DOI: 10.1038/S41571-019-0212-6
Abstract: The originally published article contained errors in the main text and in figure 1 in the reported number of patients with pathogenic or likely pathogenic germline variants. The originally reported numbers did not take into account the presence of more than one variant in an in idual patient. This has been corrected in the HTML and PDF versions of the manuscript.
Publisher: Wiley
Date: 02-2010
DOI: 10.1111/J.1365-2559.2009.03475.X
Abstract: Activation of Notch signalling results in hyperplasia and tumorigenesis in murine mammary epithelium. However, there is little information regarding the expression of Notch1 in premalignant lesions and early breast cancer. We investigated expression of Notch1 in breast cancer development and its association with molecular subtypes. Immunohistochemical expression of Notch1 was determined in a murine model of mammary carcinogenesis and in breast tissue from two cohorts of breast cancer patients, the first (n=222) comprising a histological progression series and the second an outcome series of 228 patients with operable invasive ductal carcinoma. Enhanced expression of Notch1 protein was an early event in both murine and human breast cancer development with progressive increases in expression with the development of hyperplasia and malignancy. High Notch1 was not prognostic in the outcome cohort. There was, however, a highly significant association of high Notch1 protein with the HER-2 molecular subtype of breast cancer (P=0.008). These data demonstrate that aberrant Notch regulation is an early event in mammary carcinogenesis and is associated with the HER-2 molecular subtype of breast cancer, and suggest the Notch signalling pathway may be a potential therapeutic target worthy of further investigation.
Publisher: Springer Science and Business Media LLC
Date: 02-02-2015
DOI: 10.1038/BMT.2014.313
Abstract: Thymoglobulin (TG) given with conditioning for allogeneic haematopoietic SCT (alloHSCT) is effective in reducing the risk of acute and chronic GVHD (cGVHD). Whether conventional risk factors for GVHD apply to TG-conditioned alloHSCT is unknown. We retrospectively studied 356 adults from three centres who received TG 4.5 mg/kg prior to alloHSCT for haematologic malignancy. Donors were unrelated in 64%. At 3 years, OS was 61% (95% confidence interval (CI) 55-67%), cumulative incidence of relapse was 28% (95% CI 23-33%) and non-relapse mortality was 19% (14-24%). The cumulative incidences of grade 2-4, and grade 3-4 acute GVHD were 23% (95% CI 19-28%) and 10% (95% CI 6-13%), respectively. The cumulative incidence of cGVHD requiring systemic immunosuppression (cGVHD-IS) at 3 years was 32% (95% CI 27-37%). On multivariate analysis, counterintuitively, recipient age over 40 was associated with a significantly decreased risk of cGVHD-IS (P=0.001). We report for the first time a paradoxical association of older age with reduced cGVHD in TG recipients, and conclude that traditional risk factors for GVHD may behave differently in the context of pre-transplant TG.
Publisher: Cold Spring Harbor Laboratory
Date: 22-11-2019
DOI: 10.1101/852210
Abstract: Mitochondrial diseases (MDs) are the most common group of inherited metabolic disorders and are often challenging to diagnose due to extensive genotype-phenotype heterogeneity. MDs are caused by mutations in the nuclear or mitochondrial genome, where pathogenic mitochondrial variants are usually heteroplasmic and typically at much lower allelic fraction in the blood than affected tissues. Both genomes can now be readily analysed using unbiased whole genome sequencing (WGS), but most nuclear variant detection methods fail to detect low heteroplasmy variants in the mitochondrial genome. We present mity , a bioinformatics pipeline for detecting and interpreting heteroplasmic SNVs and INDELs in the mitochondrial genome using WGS data. In 2,980 healthy controls, we observed on average 3,166× coverage in the mitochondrial genome using WGS from blood. mity utilises this high depth to detect pathogenic mitochondrial variants, even at low heteroplasmy. mity enables easy interpretation of mitochondrial variants and can be incorporated into existing diagnostic WGS pipelines. This could simplify the diagnostic pathway, avoid invasive tissue biopsies and increase the diagnostic rate for MDs and other conditions caused by impaired mitochondrial function. mity is available from github.com/KCCG/mity under an MIT license. clare.puttick@crick.ac.uk , carolyn.sue@sydney.edu.au , MCowley@ccia.org.au
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/GM482
Publisher: Springer Science and Business Media LLC
Date: 12-08-2019
DOI: 10.1038/S41467-019-10968-6
Abstract: Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2007
Publisher: Public Library of Science (PLoS)
Date: 14-10-2011
Publisher: Springer Science and Business Media LLC
Date: 28-04-2017
Publisher: Springer Science and Business Media LLC
Date: 19-02-2019
DOI: 10.1038/S41571-019-0179-3
Abstract: Cancer is a genetic disease. To date, translational cancer genomics has focused largely on somatic alterations, driven by the desire to identify targets for personalized therapy. However, therapeutically relevant information is also latent within the germline genome. In addition to cancer susceptibility, alterations present in the germ line can determine responses to both targeted and more traditional anticancer therapies, as well as their toxicities. Despite the importance of these alterations, many algorithms designed to analyse somatic mutations conversely continue to subtract information on germline genetics during analysis. In the light of low actionable yields from somatic tumour testing, a need exists for ersification of the sources of potential therapeutic biomarkers. In this Review, we summarize the literature on the therapeutic potential of alterations in the germline genome. The therapeutic value of germline information will not only be manifest as improvements in treatment but will also drive greater levels of engagement and cooperation between traditional oncology services and familial risk management clinics.
Publisher: Public Library of Science (PLoS)
Date: 29-12-2011
Publisher: Springer Science and Business Media LLC
Date: 29-07-2015
Publisher: Wiley
Date: 09-05-2014
DOI: 10.1002/IJC.28765
Abstract: The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high-density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and were capable of segregating PDAC from non-malignant pancreas, regardless of tumor cellularity. As expected, PDAC hypermethylation was most prevalent in the 5' region of genes (including the proximal promoter, 5'UTR and CpG islands). Approximately 33% DM genes showed significant inverse correlation with mRNA expression levels. Pathway analysis revealed an enrichment of aberrantly methylated genes involved in key molecular mechanisms important to PDAC: TGF-β, WNT, integrin signaling, cell adhesion, stellate cell activation and axon guidance. Given the recent discovery that SLIT-ROBO mutations play a clinically important role in PDAC, the role of epigenetic perturbation of axon guidance was pursued in more detail. Bisulfite licon deep sequencing and qRT-PCR expression analyses confirmed recurrent perturbation of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, ITGA2 and MET and suggests epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET and ITGA2 expression. Hypomethylation of MET and ITGA2 correlated with high gene expression, which was associated with poor survival. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting core signaling pathways with potential implications for the disease pathophysiology and therapy.
No related grants have been discovered for Mark Pinese.