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Pancreatic Neoplasms: HELP
Articles by David K. Chang
Based on 40 articles published since 2010
(Why 40 articles?)
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Between 2010 and 2020, D. K. Chang wrote the following 40 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Inherited susceptibility to pancreatic cancer in the era of next-generation sequencing. 2015

Humphris, Jeremy / Chang, David K / Biankin, Andrew V. ·The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, Sydney, New South Wales, Australia; Faculty of Medicine, St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales, Liverpool, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, Sydney, New South Wales, Australia; Faculty of Medicine, St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales, Liverpool, Australia. Electronic address: Andrew.Biankin@glasgow.ac.uk. ·Gastroenterology · Pubmed #25613311.

ABSTRACT: -- No abstract --

2 Editorial Can we move towards personalised pancreatic cancer therapy? 2014

Jamieson, Nigel Balfour / Chang, David K / Grimmond, Sean M / Biankin, Andrew V. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK. ·Expert Rev Gastroenterol Hepatol · Pubmed #24702631.

ABSTRACT: -- No abstract --

3 Review Molecular subtypes of pancreatic cancer. 2019

Collisson, Eric A / Bailey, Peter / Chang, David K / Biankin, Andrew V. ·University of California, San Francisco, San Francisco, CA, USA. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, Scotland, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, Scotland, UK. andrew.biankin@glasgow.ac.uk. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. andrew.biankin@glasgow.ac.uk. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia. andrew.biankin@glasgow.ac.uk. ·Nat Rev Gastroenterol Hepatol · Pubmed #30718832.

ABSTRACT: Cancers that appear morphologically similar often have dramatically different clinical features, respond variably to therapy and have a range of outcomes. Compelling evidence now demonstrates that differences in the molecular pathology of otherwise indistinguishable cancers substantially impact the clinical characteristics of the disease. Molecular subtypes now guide preclinical and clinical therapeutic development and treatment in many cancer types. The ability to predict optimal therapeutic strategies ahead of treatment improves overall patient outcomes, minimizing treatment-related morbidity and cost. Although clinical decision making based on histopathological criteria underpinned by robust data is well established in many cancer types, subtypes of pancreatic cancer do not currently inform treatment decisions. However, accumulating molecular data are defining subgroups in pancreatic cancer with distinct biology and potential subtype-specific therapeutic vulnerabilities, providing the opportunity to define a de novo clinically applicable molecular taxonomy. This Review summarizes current knowledge concerning the molecular subtyping of pancreatic cancer and explores future strategies for using a molecular taxonomy to guide therapeutic development and ultimately routine therapy with the overall goal of improving outcomes for this disease.

4 Review Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development. 2017

Dreyer, Stephan B / Chang, David K / Bailey, Peter / Biankin, Andrew V. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow, Scotland, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow, Scotland, United Kingdom. Andrew.Biankin@glasgow.ac.uk. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales, Australia. ·Clin Cancer Res · Pubmed #28373362.

ABSTRACT: Pancreatic cancer has become the third leading cause of cancer-related death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet only 20% of patients will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers and beyond that, a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient subgroups. With the development of next-generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection. Incorporating preclinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large-scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development.

5 Review Cancer Genetics and Implications for Clinical Management. 2015

Jamieson, Nigel B / Chang, David K / Biankin, Andrew V. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, Glasgow Royal Infirmary, University of Glasgow, Alexandra Parade, Glasgow G31 2ER, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Alexandra Parade, Glasgow G31 2ER, UK. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, New South Wales 2010, Australia; Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia; Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Goulburn St, Liverpool, New South Wales 2170, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, New South Wales 2010, Australia; Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia; Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Goulburn St, Liverpool, New South Wales 2170, Australia. Electronic address: andrew.biankin@glasgow.ac.uk. ·Surg Clin North Am · Pubmed #26315514.

ABSTRACT: There is now compelling evidence that the molecular heterogeneity of cancer is associated with disparate phenotypes with variable outcomes and therapeutic responsiveness to therapy in histologically indistinguishable cancers. This diversity may explain why conventional clinical trial designs have mostly failed to show efficacy when patients are enrolled in an unselected fashion. Knowledge of the molecular phenotype has the potential to improve therapeutic selection and hence the early delivery of the optimal therapeutic regimen. Resolution of the challenges associated with a more stratified approach to health care will ensure more precise diagnostics and enhance therapeutic selection, which will improve overall outcomes.

6 Review Pancreatic cancer genomics: where can the science take us? 2015

Graham, J S / Jamieson, N B / Rulach, R / Grimmond, S M / Chang, D K / Biankin, A V. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. · Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, Glasgow, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, University of Glasgow, Glasgow, United Kingdom. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia. · Department of Surgery, Bankstown Hospital, Sydney, Australia. · St Vincent's Clinical School, Faculty of Medicine, Sydney, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia. ·Clin Genet · Pubmed #25388820.

ABSTRACT: The incidence of pancreatic ductal adenocarcinoma (PDAC) is steadily increasing and the annual death-to-incidence ratio approaches one. This is a figure that has not changed for several decades. Surgery remains the only chance of cure; however, only less than 20% of patients are amenable to operative resection. Despite successful surgical resection, the majority of the patients still succumb to recurrent metastatic disease. Therefore, there is an urgent need to develop novel therapeutic strategies and to better select patients for current therapies. In this review, we will discuss current management by highlighting the landmark clinical trials that have shaped current care. We will then discuss the challenges of therapeutic development using the current randomized-controlled trial paradigm when confronted with the molecular heterogeneity of PDAC. Finally, we will discuss strategies that may help to shape the management of PDAC in the near future.

7 Review Personalising pancreas cancer treatment: When tissue is the issue. 2014

Sjoquist, Katrin M / Chin, Venessa T / Chantrill, Lorraine A / O'Connor, Chelsie / Hemmings, Chris / Chang, David K / Chou, Angela / Pajic, Marina / Johns, Amber L / Nagrial, Adnan M / Biankin, Andrew V / Yip, Desmond. ·Katrin M Sjoquist, NHMRC Clinical Trials Centre, University of Sydney, Sydney NSW 1450, Australia. ·World J Gastroenterol · Pubmed #24976722.

ABSTRACT: The treatment of advanced pancreatic cancer has not moved much beyond single agent gemcitabine until recently when protocols such as FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) and nab-paclitaxel-gemcitabine have demonstrated some improved outcomes. Advances in technology especially in massively parallel genome sequencing has progressed our understanding of the biology of pancreatic cancer especially the candidate signalling pathways that are involved in tumourogenesis and disease course. This has allowed identification of potentially actionable mutations that may be targeted by new biological agents. The heterogeneity of pancreatic cancer makes tumour tissue collection important with the aim of being able to personalise therapies for the individual as opposed to a one size fits all approach to treatment of the condition. This paper reviews the developments in this area of translational research and the ongoing clinical studies that will attempt to move this into the everyday oncology practice.

8 Review Pancreatic cancer genomics. 2014

Chang, David K / Grimmond, Sean M / Biankin, Andrew V. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, Scotland G61 1BD, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland G4 0SF, United Kingdom; The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW 2200, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, NSW 2170, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, Scotland G61 1BD, United Kingdom; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD, Australia. Electronic address: s.grimmond@imb.uq.edu.au. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, Scotland G61 1BD, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland G4 0SF, United Kingdom; The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW 2200, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, NSW 2170, Australia. Electronic address: sean.grimmond@glasgow.ac.uk. ·Curr Opin Genet Dev · Pubmed #24480245.

ABSTRACT: Pancreatic cancer is one of the most lethal malignancies. The overall median survival even with treatment is only 6-9 months, with almost 90% succumbing to the disease within a year of diagnosis. It is characterised by an intense desmoplastic stroma that may contribute to therapeutic resistance, and poses significant challenges for genomic sequencing studies. It is recalcitrant to almost all therapies and consequently remains the fourth leading cause of cancer death in Western societies. Genomic studies are unveiling a vast heterogeneity of mutated genes, and this diversity may explain why conventional clinical trial designs have mostly failed to demonstrate efficacy in unselected patients. Those that are available offer only marginal benefits overall, but are associated with clinically significant responses in as yet undefined subgroups. This chapter describes our current understanding of the genomics of pancreatic cancer and the potential impact of these findings on our approaches to treatment.

9 Review Understanding pancreatic cancer genomes. 2013

Cowley, Mark J / Chang, David K / Pajic, Marina / Johns, Amber L / Waddell, Nicola / Grimmond, Sean M / Biankin, Andrew V. ·The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, Australia; Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia. ·J Hepatobiliary Pancreat Sci · Pubmed #23660961.

ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in our society, with a mortality that virtually parallels its incidence, a median survival of <12 months even with maximal therapy, and a 5-year survival rate of <5 %. The diversity of clinical outcomes and the molecular heterogeneity of histopathologically similar cancer types, incomplete knowledge of the genomic aberrations that drive carcinogenesis and the lack of therapeutics that specifically target most known genomic aberrations necessitates large-scale detailed analysis of cancer genomes to identify novel potential therapeutic strategies. As part of the International Cancer Genome Consortium (ICGC), the Australian Pancreatic Cancer Genome Initiative (APGI) used exomic sequencing and copy number analysis to define genomic aberrations that characterize a large, clinically focused, prospectively accrued cohort of patients with pancreatic cancer. The cohort consisted of early (clinical stages I and II) non-pre-treated patients with pancreatic ductal adenocarcinoma who underwent operative resection with curative intent. We devised approaches to adjust for low epithelial content in primary tumours and to define the genomic landscape of pancreatic cancer to identify novel candidate driver genes and mechanisms. We aim to develop stratified, molecular phenotype-guided therapeutic strategies using existing therapeutics that are either rescued, repurposed, in development, or are known to be effective in an undefined subgroup of PC patients. These are then tested in primary patient-derived xenografts and cell lines from the above deeply characterized cohort. In addition, we return information to treating clinicians that influences patient care and are launching a clinical trial called IMPaCT (Individualized Molecular Pancreatic Cancer Therapy). This umbrella design trial randomizes patients with metastatic disease to either standard first-line therapy with gemcitabine, or a molecular phenotype-guided approach using next-generation sequencing strategies to screen for actionable mutations defined through the ICGC effort.

10 Clinical Trial Precision Medicine for Advanced Pancreas Cancer: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial. 2015

Chantrill, Lorraine A / Nagrial, Adnan M / Watson, Clare / Johns, Amber L / Martyn-Smith, Mona / Simpson, Skye / Mead, Scott / Jones, Marc D / Samra, Jaswinder S / Gill, Anthony J / Watson, Nicole / Chin, Venessa T / Humphris, Jeremy L / Chou, Angela / Brown, Belinda / Morey, Adrienne / Pajic, Marina / Grimmond, Sean M / Chang, David K / Thomas, David / Sebastian, Lucille / Sjoquist, Katrin / Yip, Sonia / Pavlakis, Nick / Asghari, Ray / Harvey, Sandra / Grimison, Peter / Simes, John / Biankin, Andrew V / Anonymous5550827 / Anonymous5560827. ·The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Macarthur Cancer Therapy Centre, Campbelltown, New South Wales, Australia. Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. andrew.biankin@glasgow.ac.uk l.chantrill@garvan.org.au. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Prince of Wales Hospital, Randwick, New South Wales, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland. · University of Sydney, New South Wales, Australia. Macquarie University Hospital, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Department of Anatomical Pathology, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland. Department of Surgery, Bankstown Hospital, Sydney, New South Wales, Australia. South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, New South Wales, Australia. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. · Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. · Northern Sydney Cancer Centre, Royal North Shore Hospital, New South Wales, Australia. · Bankstown Cancer Centre, Bankstown, New South Wales, Australia. · Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia. · Sydney Catalyst Translational Cancer Research Centre, University of Sydney, Camperdown, New South Wales, Australia. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland. Department of Surgery, Bankstown Hospital, Sydney, New South Wales, Australia. South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, New South Wales, Australia. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. andrew.biankin@glasgow.ac.uk l.chantrill@garvan.org.au. ·Clin Cancer Res · Pubmed #25896973.

ABSTRACT: PURPOSE: Personalized medicine strategies using genomic profiling are particularly pertinent for pancreas cancer. The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was initially designed to exploit results from genome sequencing of pancreatic cancer under the auspices of the International Cancer Genome Consortium (ICGC) in Australia. Sequencing revealed small subsets of patients with aberrations in their tumor genome that could be targeted with currently available therapies. EXPERIMENTAL DESIGN: The pilot stage of the IMPaCT trial assessed the feasibility of acquiring suitable tumor specimens for molecular analysis and returning high-quality actionable genomic data within a clinically acceptable timeframe. We screened for three molecular targets: HER2 amplification; KRAS wild-type; and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM). RESULTS: Tumor biopsy and archived tumor samples were collected from 93 patients and 76 were screened. To date 22 candidate cases have been identified: 14 KRAS wild-type, 5 cases of HER2 amplification, 2 mutations in BRCA2, and 1 ATM mutation. Median time from consent to the return of validated results was 21.5 days. An inability to obtain a biopsy or insufficient tumor content in the available specimen were common reasons for patient exclusion from molecular analysis while deteriorating performance status prohibited a number of patients from proceeding in the study. CONCLUSIONS: Documenting the feasibility of acquiring and screening biospecimens for actionable molecular targets in real time will aid other groups embarking on similar trials. Key elements include the need to better prescreen patients, screen more patients, and offer more attractive clinical trial options.

11 Article Feasibility and clinical utility of endoscopic ultrasound guided biopsy of pancreatic cancer for next-generation molecular profiling. 2019

Dreyer, Stephan B / Jamieson, Nigel B / Evers, Lisa / Duthie, Fraser / Cooke, Susie / Marshall, John / Beraldi, Dario / Knight, Stephen / Upstill-Goddard, Rosanna / Dickson, Euan J / Carter, C Ross / McKay, Colin J / Biankin, Andrew V / Chang, David K. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · Department of Clinical Surgery, University of Edinburgh, Edinburgh, UK. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. david.chang@glasgow.ac.uk. ·Chin Clin Oncol · Pubmed #31070037.

ABSTRACT: Next-generation sequencing is enabling molecularly guided therapy for many cancer types, yet failure rates remain relatively high in pancreatic cancer (PC). The aim of this study is to investigate the feasibility of genomic profiling using endoscopic ultrasound (EUS) biopsy samples to facilitate personalised therapy for PC. Ninty-five patients underwent additional research biopsies at the time of diagnostic EUS. Diagnostic formalin-fixed (FFPE) and fresh frozen EUS samples underwent DNA extraction, quantification and targeted gene sequencing. Whole genome (WGS) and RNA sequencing was performed as proof of concept. Only 2 patients (2%) with a diagnosis of PC had insufficient material for targeted sequencing in both FFPE and frozen specimens. Targeted panel sequencing (n=54) revealed mutations in PC genes (KRAS, GNAS, TP53, CDKN2A, SMAD4) in patients with histological evidence of PC, including potentially actionable mutations (BRCA1, BRCA2, ATM, BRAF). WGS (n=5) of EUS samples revealed mutational signatures that are potential biomarkers of therapeutic responsiveness. RNA sequencing (n=35) segregated patients into clinically relevant molecular subtypes based on transcriptome. Integrated multi-omic analysis of PC using standard EUS guided biopsies offers clinical utility to guide personalized therapy and study the molecular pathology in all patients with PC.

12 Article Defining the molecular pathology of pancreatic body and tail adenocarcinoma. 2018

Dreyer, S B / Jamieson, N B / Upstill-Goddard, R / Bailey, P J / McKay, C J / Anonymous3830933 / Biankin, A V / Chang, D K. ·West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. ·Br J Surg · Pubmed #29341146.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas. METHODS: Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study. RESULTS: Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole-genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial-to-mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer. CONCLUSION: PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.

13 Article Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. 2018

Chou, Angela / Froio, Danielle / Nagrial, Adnan M / Parkin, Ashleigh / Murphy, Kendelle J / Chin, Venessa T / Wohl, Dalia / Steinmann, Angela / Stark, Rhys / Drury, Alison / Walters, Stacey N / Vennin, Claire / Burgess, Andrew / Pinese, Mark / Chantrill, Lorraine A / Cowley, Mark J / Molloy, Timothy J / Anonymous170925 / Waddell, Nicola / Johns, Amber / Grimmond, Sean M / Chang, David K / Biankin, Andrew V / Sansom, Owen J / Morton, Jennifer P / Grey, Shane T / Cox, Thomas R / Turchini, John / Samra, Jaswinder / Clarke, Stephen J / Timpson, Paul / Gill, Anthony J / Pajic, Marina. ·The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · Faculty of Medicine, St Vincent's Clinical School, University of NSW, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, SYDPATH, Darlinghurst, Australia. · Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. · St. Vincent's Hospital, Darlinghurst, Australia. · St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales, Australia. · Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Queensland, Australia. · University of Melbourne, Melbourne, Victoria, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Department of Surgery, Cancer Research UK, Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. · Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, New South Wales, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia. ·Gut · Pubmed #29080858.

ABSTRACT: OBJECTIVE: Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. DESIGN: Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens). RESULTS: Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. CONCLUSION: This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.

14 Article Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. 2017

Feigin, Michael E / Garvin, Tyler / Bailey, Peter / Waddell, Nicola / Chang, David K / Kelley, David R / Shuai, Shimin / Gallinger, Steven / McPherson, John D / Grimmond, Sean M / Khurana, Ekta / Stein, Lincoln D / Biankin, Andrew V / Schatz, Michael C / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York, USA. · Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. · The Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales, Australia. · Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. · Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Division of General Surgery, Toronto General Hospital, Toronto, Ontario, Canada. · Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Sandra and Edward Meyer Cancer Center, Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA. · Informatics and Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland, UK. · Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA. · Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA. ·Nat Genet · Pubmed #28481342.

ABSTRACT: The contributions of coding mutations to tumorigenesis are relatively well known; however, little is known about somatic alterations in noncoding DNA. Here we describe GECCO (Genomic Enrichment Computational Clustering Operation) to analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas (PDAs) and identify commonly mutated regulatory regions. We find recurrent noncoding mutations to be enriched in PDA pathways, including axon guidance and cell adhesion, and newly identified processes, including transcription and homeobox genes. We identified mutations in protein binding sites correlating with differential expression of proximal genes and experimentally validated effects of mutations on expression. We developed an expression modulation score that quantifies the strength of gene regulation imposed by each class of regulatory elements, and found the strongest elements were most frequently mutated, suggesting a selective advantage. Our detailed single-cancer analysis of noncoding alterations identifies regulatory mutations as candidates for diagnostic and prognostic markers, and suggests new mechanisms for tumor evolution.

15 Article Lost in translation: returning germline genetic results in genome-scale cancer research. 2017

Johns, Amber L / McKay, Skye H / Humphris, Jeremy L / Pinese, Mark / Chantrill, Lorraine A / Mead, R Scott / Tucker, Katherine / Andrews, Lesley / Goodwin, Annabel / Leonard, Conrad / High, Hilda A / Nones, Katia / Patch, Ann-Marie / Merrett, Neil D / Pavlakis, Nick / Kassahn, Karin S / Samra, Jaswinder S / Miller, David K / Chang, David K / Pajic, Marina / Anonymous6590904 / Pearson, John V / Grimmond, Sean M / Waddell, Nicola / Zeps, Nikolajs / Gill, Anthony J / Biankin, Andrew V. ·Cancer Research Program, Garvan Institute of Medical Research, Kinghorn Cancer Centre, Sydney, Australia. · St Vincents Hospital, Darlinghurst, Australia. · Western Sydney University Clinical School, Sydney, Australia. · Genetics Department, SEALS Pathology, Prince of Wales Hospital, Randwick, Sydney, Australia. · School of Medicine, University of New South Wales, Sydney, Australia. · Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Sydney, Australia. · Cancer Genetics Department, Royal Prince Alfred Hospital and Liverpool Hospital, Sydney, NSW, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Australia. · Sydney Cancer Genetics, Sydney, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, Australia. · Division of Surgery, School of Medicine, Western Sydney University, Sydney, Australia. · Department of Medical Oncology, Royal North Shore Hospital and Faculty of Medicine, University of Sydney, Sydney, Australia. · Genetic and Molecular Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, Adelaide, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, Australia. · Illumina Inc, 5200 Illumina Way, San Diego, CA, 92122, USA. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia. · University of Melbourne, Parkville, Australia. · St John of God Subiaco, Perth, Australia. · School of Surgery, The University of Western Australia, Perth, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Australia and University of Sydney, Sydney, Australia. · Cancer Research Program, Garvan Institute of Medical Research, Kinghorn Cancer Centre, Sydney, Australia. andrew.biankin@glasgow.ac.uk. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. andrew.biankin@glasgow.ac.uk. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia. andrew.biankin@glasgow.ac.uk. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, UK. andrew.biankin@glasgow.ac.uk. ·Genome Med · Pubmed #28454591.

ABSTRACT: BACKGROUND: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. METHODS: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. RESULTS: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. CONCLUSION: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.

16 Article BRCA2 secondary mutation-mediated resistance to platinum and PARP inhibitor-based therapy in pancreatic cancer. 2017

Pishvaian, Michael J / Biankin, Andrew V / Bailey, Peter / Chang, David K / Laheru, Daniel / Wolfgang, Christopher L / Brody, Jonathan R. ·Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Liverpool, New South Wales 2170, Australia. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. · Department of Surgery, Johns Hopkins University, Baltimore, MD, USA. · Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. ·Br J Cancer · Pubmed #28291774.

ABSTRACT: BACKGROUND: Pancreatic cancer has become the third leading cause of cancer death with minimal improvements in outcome for over 40 years. Recent trials of therapies that target-defective DNA maintenance using poly (ADP-ribose) polymerase (PARP) inhibitors are showing promising results, yet invariably patients recur and succumb to disease. Mechanisms of resistance to platinum-based and PARP inhibitor therapy in other cancer types include secondary mutations, which restore the integrity of DNA repair through an increasing number of different mechanisms. METHODS: Here we present a case of a 63-year-old female patient with a germ line pathogenic BRCA2 mutation (6714 deletion) who developed pancreatic cancer and had an exceptional response to platinum and PARP inhibitor therapy. Through next-generation sequencing and clinical follow-up, we correlated tumour response and resistance to the BRCA2 mutational status in the tumour. RESULTS: Initially, the patient had an exceptional response to platinum and PARP inhibitor therapy, most likely due to the BRCA2 mutation. However, the primary lesion recurred while on PARP inhibitor therapy and contained a secondary mutation in BRCA2, which mostly likely restored BRCA2 function in PARP inhibitor-resistant tumour cells. CONCLUSIONS: To our knowledge, this is the first report of a BRCA2 reversion mutation that conferred resistance to PARP inhibitor-based therapy in a pancreatic ductal adenocarcinoma patient. Future studies are needed to understand this important mechanism of resistance and how it may impact the choice of therapy for patients with pancreatic cancer.

17 Article An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer. 2017

Vallejo, Adrian / Perurena, Naiara / Guruceaga, Elisabet / Mazur, Pawel K / Martinez-Canarias, Susana / Zandueta, Carolina / Valencia, Karmele / Arricibita, Andrea / Gwinn, Dana / Sayles, Leanne C / Chuang, Chen-Hua / Guembe, Laura / Bailey, Peter / Chang, David K / Biankin, Andrew / Ponz-Sarvise, Mariano / Andersen, Jesper B / Khatri, Purvesh / Bozec, Aline / Sweet-Cordero, E Alejandro / Sage, Julien / Lecanda, Fernando / Vicent, Silve. ·University of Navarra, Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona 31010, Spain. · University of Navarra, Center for Applied Medical Research, Proteomics, Genomics and Bioinformatics Core Facility, Pamplona 31010, Spain. · Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. · Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA. · Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA. · University of Navarra, Center for Applied Medical Research, Morphology Unit, Pamplona 31010, Spain. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · Clínica Universidad de Navarra, Department of Medical Oncology, Pamplona 31008, Spain. · Biotech Research and Innovation Center, University of Copenhagen, Copenhagen, DK-2200, Denmark. · Stanford Institute for Immunity, Transplantation and Infection, Stanford, California 94305, USA. · Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, California 94305, USA. · Department of Internal Medicine 3 and Institute of Clinical Immunology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany. · IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain. · University of Navarra, Department of Histology and Pathology, Pamplona 31008, Spain. ·Nat Commun · Pubmed #28220783.

ABSTRACT: KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers.

18 Article Whole-genome landscape of pancreatic neuroendocrine tumours. 2017

Scarpa, Aldo / Chang, David K / Nones, Katia / Corbo, Vincenzo / Patch, Ann-Marie / Bailey, Peter / Lawlor, Rita T / Johns, Amber L / Miller, David K / Mafficini, Andrea / Rusev, Borislav / Scardoni, Maria / Antonello, Davide / Barbi, Stefano / Sikora, Katarzyna O / Cingarlini, Sara / Vicentini, Caterina / McKay, Skye / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / McLean, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Wilson, Peter J / Anderson, Matthew J / Fink, J Lynn / Newell, Felicity / Waddell, Nick / Holmes, Oliver / Kazakoff, Stephen H / Leonard, Conrad / Wood, Scott / Xu, Qinying / Nagaraj, Shivashankar Hiriyur / Amato, Eliana / Dalai, Irene / Bersani, Samantha / Cataldo, Ivana / Dei Tos, Angelo P / Capelli, Paola / Davì, Maria Vittoria / Landoni, Luca / Malpaga, Anna / Miotto, Marco / Whitehall, Vicki L J / Leggett, Barbara A / Harris, Janelle L / Harris, Jonathan / Jones, Marc D / Humphris, Jeremy / Chantrill, Lorraine A / Chin, Venessa / Nagrial, Adnan M / Pajic, Marina / Scarlett, Christopher J / Pinho, Andreia / Rooman, Ilse / Toon, Christopher / Wu, Jianmin / Pinese, Mark / Cowley, Mark / Barbour, Andrew / Mawson, Amanda / Humphrey, Emily S / Colvin, Emily K / Chou, Angela / Lovell, Jessica A / Jamieson, Nigel B / Duthie, Fraser / Gingras, Marie-Claude / Fisher, William E / Dagg, Rebecca A / Lau, Loretta M S / Lee, Michael / Pickett, Hilda A / Reddel, Roger R / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Epari, Krishna / Nguyen, Nam Q / Zeps, Nikolajs / Falconi, Massimo / Simbolo, Michele / Butturini, Giovanni / Van Buren, George / Partelli, Stefano / Fassan, Matteo / Anonymous6880896 / Khanna, Kum Kum / Gill, Anthony J / Wheeler, David A / Gibbs, Richard A / Musgrove, Elizabeth A / Bassi, Claudio / Tortora, Giampaolo / Pederzoli, Paolo / Pearson, John V / Waddell, Nicola / Biankin, Andrew V / Grimmond, Sean M. ·ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · Medical Oncology, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology, General Hospital of Treviso, Department of Medicine, University of Padua, Italy. · Department of Medicine, Section of Endocrinology, University and Hospital Trust of Verona, Verona, Italy. · The University of Queensland, School of Medicine, Brisbane 4006, Australia. · Pathology Queensland, Brisbane 4006, Australia. · Royal Brisbane and Women's Hospital, Department of Gastroenterology and Hepatology, Brisbane 4006, Australia. · Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. · School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Centre for Cancer Bioinformatics, Peking University Cancer Hospital &Institute, Beijing 100142, China. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · Department of Anatomical Pathology. St Vincent's Hospital, Sydney, New South Wales 2010, Australia. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. · Department of Pathology, Queen Elizabeth University Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. · Michael E. DeBakey Department of Surgery and The Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA. · Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia. · Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales 2145, Australia. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · University of Sydney. Sydney, New South Wales 2006, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. · School of Medicine, Western Sydney University, Penrith, New South Wales 2175, Australia. · Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands, Western Australia 6009, Australia. · St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. · Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia 6008, Australia. · University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, 3010, Victoria, Australia. ·Nature · Pubmed #28199314.

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.

19 Article Hypermutation In Pancreatic Cancer. 2017

Humphris, Jeremy L / Patch, Ann-Marie / Nones, Katia / Bailey, Peter J / Johns, Amber L / McKay, Skye / Chang, David K / Miller, David K / Pajic, Marina / Kassahn, Karin S / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Stone, Andrew / Wilson, Peter J / Anderson, Matthew / Fink, J Lynn / Holmes, Oliver / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Mead, Ronald S / Xu, Qinying / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Nagrial, Adnan M / Chin, Venessa T / Chantrill, Lorraine A / Mawson, Amanda / Chou, Angela / Scarlett, Christopher J / Pinho, Andreia V / Rooman, Ilse / Giry-Laterriere, Marc / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Jamieson, Nigel B / McKay, Colin J / Carter, C Ross / Dickson, Euan J / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Morton, Jennifer P / Sansom, Owen J / Grützmann, Robert / Hruban, Ralph H / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Schulick, Richard D / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Rusev, Borislav / Corbo, Vincenzo / Salvia, Roberto / Cataldo, Ivana / Tortora, Giampaolo / Tempero, Margaret A / Anonymous5070887 / Hofmann, Oliver / Eshleman, James R / Pilarsky, Christian / Scarpa, Aldo / Musgrove, Elizabeth A / Gill, Anthony J / Pearson, John V / Grimmond, Sean M / Waddell, Nicola / Biankin, Andrew V. ·The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Genetic and Molecular Pathology, Adelaide, South Australia, Australia; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; South Eastern Area Laboratory Services Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia; Sonic Genetics, Douglass Hanly Moir Pathology, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Department of Anatomical Pathology, SydPath, St Vincent's Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. · Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; School of Medicine, Western Sydney University, Penrith, New South Wales, Australia. · Department of Surgery, Fiona Stanley Hospital, Murdoch, Washington. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia. · Department of Surgery, Princess Alexandra Hospital, Woollongabba, Queensland, Australia. · School of Surgery, University of Western Australia, Australia and St John of God Pathology, Subiaco, Washington. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. · Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde National Health Service, Glasgow, United Kingdom. · Greater Glasgow and Clyde Bio-repository, Pathology Department, Queen Elizabeth University Hospital, Glasgow, United Kingdom. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute for Cancer Science, University of Glasgow, Glasgow, United Kingdom. · Universitätsklinikum Erlangen, Erlangen, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. · Division of Hematology and Oncology, University of California, San Francisco, California. · Australian Pancreatic Cancer Genome Initiative. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Universitätsklinikum Erlangen, Department of Surgery, University of Erlangen-Nueremberg, Germany. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. Electronic address: nic.waddell@qimrberghofer.edu.au. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. Electronic address: andrew.biankin@glasgow.ac.uk. ·Gastroenterology · Pubmed #27856273.

ABSTRACT: Pancreatic cancer is molecularly diverse, 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 individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

20 Article Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma. 2016

Bailey, Peter / Chang, David K / Forget, Marie-Andrée / Lucas, Francis A San / Alvarez, Hector A / Haymaker, Cara / Chattopadhyay, Chandrani / Kim, Sun-Hee / Ekmekcioglu, Suhendan / Grimm, Elizabeth A / Biankin, Andrew V / Hwu, Patrick / Maitra, Anirban / Roszik, Jason. ·Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, United Kingdom. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. · Departments of Pathology and Translational Molecular Pathology, Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. ·Sci Rep · Pubmed #27762323.

ABSTRACT: Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues.

21 Article CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. 2016

Steele, Colin W / Karim, Saadia A / Leach, Joshua D G / Bailey, Peter / Upstill-Goddard, Rosanna / Rishi, Loveena / Foth, Mona / Bryson, Sheila / McDaid, Karen / Wilson, Zena / Eberlein, Catherine / Candido, Juliana B / Clarke, Mairi / Nixon, Colin / Connelly, John / Jamieson, Nigel / Carter, C Ross / Balkwill, Frances / Chang, David K / Evans, T R Jeffry / Strathdee, Douglas / Biankin, Andrew V / Nibbs, Robert J B / Barry, Simon T / Sansom, Owen J / Morton, Jennifer P. ·Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. · Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK. · Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK. · Centre for Cancer and Inflammation, Barts Cancer Institute, London EC1M 6BQ, UK. · Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8QQ UK. · Department of Surgery, Glasgow Royal Infirmary, Glasgow G4 0SF, UK. · Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK. · Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK. Electronic address: o.sansom@beatson.gla.ac.uk. ·Cancer Cell · Pubmed #27265504.

ABSTRACT: CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that CXCR2 signaling is upregulated in human pancreatic cancer, predominantly in neutrophil/myeloid-derived suppressor cells, but rarely in tumor cells. Genetic ablation or inhibition of CXCR2 abrogated metastasis, but only inhibition slowed tumorigenesis. Depletion of neutrophils/myeloid-derived suppressor cells also suppressed metastasis suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche. Importantly, loss or inhibition of CXCR2 improved T cell entry, and combined inhibition of CXCR2 and PD1 in mice with established disease significantly extended survival. We show that CXCR2 signaling in the myeloid compartment can promote pancreatic tumorigenesis and is required for pancreatic cancer metastasis, making it an excellent therapeutic target.

22 Article Resolution of Novel Pancreatic Ductal Adenocarcinoma Subtypes by Global Phosphotyrosine Profiling. 2016

Humphrey, Emily S / Su, Shih-Ping / Nagrial, Adnan M / Hochgräfe, Falko / Pajic, Marina / Lehrbach, Gillian M / Parton, Robert G / Yap, Alpha S / Horvath, Lisa G / Chang, David K / Biankin, Andrew V / Wu, Jianmin / Daly, Roger J. ·From the ‡Cancer Division and Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; §St Vincent's Hospital Clinical School, Faculty of Medicine, University of New South Wales, NSW 2052, Australia; · ¶Cancer Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Level 1, Building 77, Monash University, VIC 3800, Australia; · ‖Competence Center Functional Genomics, University of Greifswald, F.-L-Jahnstr. 15, 17489 Greifswald, Germany; · From the ‡Cancer Division and Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; · **Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane QLD 4072, Australia; · From the ‡Cancer Division and Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; ‡‡Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW 2050, Australia; · §§Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; · §§Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; andrew.biankin@glasgow.ac.uk. · ¶¶Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, 52 Fu-Cheng Road, Hai-Dian District, Beijing 100142, China From the ‡Cancer Division and Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; §St Vincent's Hospital Clinical School, Faculty of Medicine, University of New South Wales, NSW 2052, Australia; roger.daly@monash.edu wujm@bjmu.edu.cn. · ¶Cancer Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Level 1, Building 77, Monash University, VIC 3800, Australia; roger.daly@monash.edu wujm@bjmu.edu.cn. ·Mol Cell Proteomics · Pubmed #27259358.

ABSTRACT: Comprehensive characterization of signaling in pancreatic ductal adenocarcinoma (PDAC) promises to enhance our understanding of the molecular aberrations driving this devastating disease, and may identify novel therapeutic targets as well as biomarkers that enable stratification of patients for optimal therapy. Here, we use immunoaffinity-coupled high-resolution mass spectrometry to characterize global tyrosine phosphorylation patterns across two large panels of human PDAC cell lines: the ATCC series (19 cell lines) and TKCC series (17 cell lines). This resulted in the identification and quantification of over 1800 class 1 tyrosine phosphorylation sites and the consistent segregation of both PDAC cell line series into three subtypes with distinct tyrosine phosphorylation profiles. Subtype-selective signaling networks were characterized by identification of subtype-enriched phosphosites together with pathway and network analyses. This revealed that the three subtypes characteristic of the ATCC series were associated with perturbations in signaling networks associated with cell-cell adhesion and epithelial-mesenchyme transition, mRNA metabolism, and receptor tyrosine kinase (RTK) signaling, respectively. Specifically, the third subtype exhibited enhanced tyrosine phosphorylation of multiple RTKs including the EGFR, ERBB3 and MET. Interestingly, a similar RTK-enriched subtype was identified in the TKCC series, and 'classifier' sites for each series identified using Random Forest models were able to predict the subtypes of the alternate series with high accuracy, highlighting the conservation of the three subtypes across the two series. Finally, RTK-enriched cell lines from both series exhibited enhanced sensitivity to the small molecule EGFR inhibitor erlotinib, indicating that their phosphosignature may provide a predictive biomarker for response to this targeted therapy. These studies highlight how resolution of subtype-selective signaling networks can provide a novel taxonomy for particular cancers, and provide insights into PDAC biology that can be exploited for improved patient management.

23 Article Genomic analyses identify molecular subtypes of pancreatic cancer. 2016

Bailey, Peter / Chang, David K / Nones, Katia / Johns, Amber L / Patch, Ann-Marie / Gingras, Marie-Claude / Miller, David K / Christ, Angelika N / Bruxner, Tim J C / Quinn, Michael C / Nourse, Craig / Murtaugh, L Charles / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourbakhsh, Ehsan / Wani, Shivangi / Fink, Lynn / Holmes, Oliver / Chin, Venessa / Anderson, Matthew J / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Xu, Qinying / Wilson, Peter J / Cloonan, Nicole / Kassahn, Karin S / Taylor, Darrin / Quek, Kelly / Robertson, Alan / Pantano, Lorena / Mincarelli, Laura / Sanchez, Luis N / Evers, Lisa / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Colvin, Emily K / Nagrial, Adnan M / Humphrey, Emily S / Chantrill, Lorraine A / Mawson, Amanda / Humphris, Jeremy / Chou, Angela / Pajic, Marina / Scarlett, Christopher J / Pinho, Andreia V / Giry-Laterriere, Marc / Rooman, Ilse / Samra, Jaswinder S / Kench, James G / Lovell, Jessica A / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Moran-Jones, Kim / Jamieson, Nigel B / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Grützmann, Robert / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Corbo, Vincenzo / Bassi, Claudio / Rusev, Borislav / Capelli, Paola / Salvia, Roberto / Tortora, Giampaolo / Mukhopadhyay, Debabrata / Petersen, Gloria M / Anonymous2640859 / Munzy, Donna M / Fisher, William E / Karim, Saadia A / Eshleman, James R / Hruban, Ralph H / Pilarsky, Christian / Morton, Jennifer P / Sansom, Owen J / Scarpa, Aldo / Musgrove, Elizabeth A / Bailey, Ulla-Maja Hagbo / Hofmann, Oliver / Sutherland, Robert L / Wheeler, David A / Gill, Anthony J / Gibbs, Richard A / Pearson, John V / Waddell, Nicola / Biankin, Andrew V / Grimmond, Sean M. ·Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA. · Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia. · School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia. · Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. · Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia. · Department of Pathology. SydPath, St Vincent's Hospital, Sydney, NSW 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia. · School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · University of Sydney, Sydney, New South Wales 2006, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia. · School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia. · Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. · Department of Pathology, Southern General Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. · GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK. · Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. · Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA. · The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. · Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK. · University of Melbourne, Parkville, Victoria 3010, Australia. ·Nature · Pubmed #26909576.

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.

24 Article Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation. 2016

Gingras, Marie-Claude / Covington, Kyle R / Chang, David K / Donehower, Lawrence A / Gill, Anthony J / Ittmann, Michael M / Creighton, Chad J / Johns, Amber L / Shinbrot, Eve / Dewal, Ninad / Fisher, William E / Anonymous400856 / Pilarsky, Christian / Grützmann, Robert / Overman, Michael J / Jamieson, Nigel B / Van Buren, George / Drummond, Jennifer / Walker, Kimberly / Hampton, Oliver A / Xi, Liu / Muzny, Donna M / Doddapaneni, Harsha / Lee, Sandra L / Bellair, Michelle / Hu, Jianhong / Han, Yi / Dinh, Huyen H / Dahdouli, Mike / Samra, Jaswinder S / Bailey, Peter / Waddell, Nicola / Pearson, John V / Harliwong, Ivon / Wang, Huamin / Aust, Daniela / Oien, Karin A / Hruban, Ralph H / Hodges, Sally E / McElhany, Amy / Saengboonmee, Charupong / Duthie, Fraser R / Grimmond, Sean M / Biankin, Andrew V / Wheeler, David A / Gibbs, Richard A. ·Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: mgingras@bcm.edu. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK; The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, NSW 2170, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. · The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Michael E. DeBakey Department of Veterans Affairs Medical Center, Houston, TX 77030, USA. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. · The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; The Elkins Pancreas Center at Baylor College of Medicine, Houston, TX 77030, USA. · Department of Surgery, TU Dresden, 01307 Dresden, Germany. · Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK; Academic Unit of Surgery, Institute of Cancer Sciences, Glasgow Royal Infirmary, Level 2, New Lister Building, University of Glasgow, Glasgow G31 2ER, UK. · Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia; QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. · Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Pathology, TU Dresden, 01307 Dresden, Germany. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; Department of Pathology, Southern General Hospital, Greater Glasgow and Clyde NHS, Glasgow G51 4TF, UK. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; The Elkins Pancreas Center at Baylor College of Medicine, Houston, TX 77030, USA. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: wheeler@bcm.edu. ·Cell Rep · Pubmed #26804919.

ABSTRACT: The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

25 Article Whole genomes redefine the mutational landscape of pancreatic cancer. 2015

Waddell, Nicola / Pajic, Marina / Patch, Ann-Marie / Chang, David K / Kassahn, Karin S / Bailey, Peter / Johns, Amber L / Miller, David / Nones, Katia / Quek, Kelly / Quinn, Michael C J / Robertson, Alan J / Fadlullah, Muhammad Z H / Bruxner, Tim J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Wani, Shivangi / Wilson, Peter J / Markham, Emma / Cloonan, Nicole / Anderson, Matthew J / Fink, J Lynn / Holmes, Oliver / Kazakoff, Stephen H / Leonard, Conrad / Newell, Felicity / Poudel, Barsha / Song, Sarah / Taylor, Darrin / Waddell, Nick / Wood, Scott / Xu, Qinying / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Lee, Hong C / Jones, Marc D / Nagrial, Adnan M / Humphris, Jeremy / Chantrill, Lorraine A / Chin, Venessa / Steinmann, Angela M / Mawson, Amanda / Humphrey, Emily S / Colvin, Emily K / Chou, Angela / Scarlett, Christopher J / Pinho, Andreia V / Giry-Laterriere, Marc / Rooman, Ilse / Samra, Jaswinder S / Kench, James G / Pettitt, Jessica A / Merrett, Neil D / Toon, Christopher / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Jamieson, Nigel B / Graham, Janet S / Niclou, Simone P / Bjerkvig, Rolf / Grützmann, Robert / Aust, Daniela / Hruban, Ralph H / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Corbo, Vincenzo / Bassi, Claudio / Falconi, Massimo / Zamboni, Giuseppe / Tortora, Giampaolo / Tempero, Margaret A / Anonymous400822 / Gill, Anthony J / Eshleman, James R / Pilarsky, Christian / Scarpa, Aldo / Musgrove, Elizabeth A / Pearson, John V / Biankin, Andrew V / Grimmond, Sean M. ·1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia [2] QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia. · 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2010, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia [3] South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia [4] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia [2] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] Department of Anatomical Pathology, St Vincent's Hospital, Sydney, New South Wales 2010, Australia. · 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · 1] Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia [2] University of Sydney, Sydney, New South Wales 2006, Australia. · 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] University of Sydney, Sydney, New South Wales 2006, Australia [3] Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. · 1] Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia [2] School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia. · Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · 1] School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands 6009, Australia [2] St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia [3] Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia 6008, Australia. · 1] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK [2] Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK [3] West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · 1] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK [2] Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. · Norlux Neuro-Oncology Laboratory, CRP-Santé Luxembourg, 84 Val Fleuri, L-1526, Luxembourg. · Norlux Neuro-Oncology, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5019 Bergen, Norway. · Departments of Surgery and Pathology, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston Texas 77030, USA. · The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · 1] ARC-NET Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy [2] Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy. · ARC-NET Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Surgery and Oncology, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · 1] Department of Surgery and Oncology, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy [2] Departments of Surgery and Pathology, Ospedale Sacro Cuore Don Calabria Negrar, Verona 37024, Italy. · 1] Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy [2] Departments of Surgery and Pathology, Ospedale Sacro Cuore Don Calabria Negrar, Verona 37024, Italy. · Department of Oncology, University and Hospital Trust of Verona, Verona 37134, Italy. · Division of Hematology and Oncology, University of California, San Francisco, California 94122, USA. · 1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] University of Sydney, Sydney, New South Wales 2006, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. ·Nature · Pubmed #25719666.

ABSTRACT: Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

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