Journal
NATURE
Volume 518, Issue 7540, Pages 495-501Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature14169
Keywords
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Categories
Funding
- National Health and Medical Research Council of Australia (NHMRC) [631701, 535903, 427601]
- Queensland Government (NIRAP)
- University of Queensland
- Institute for Molecular Bioscience
- Cancer Research UK [C596/A18076, C29717/A17263]
- Australian Government: Department of Innovation, Industry, Science and Research (DIISR)
- Australian Cancer Research Foundation (ACRF)
- Cancer Council NSW [SRP06-01, SRP11-01. ICGC]
- Cancer Institute NSW [10/ECF/2-26, 06/ECF/1-24, 09/CDF/2-40, 07/CDF/1-03, 10/CRF/1-01, 08/RSA/1-15, 07/CDF/1-28, 10/CDF/2-26, 10/FRL/2-03, 06/RSA/1-05, 09/RIG/1-02, 10/TPG/1-04, 11/REG/1-10, 11/CDF/3-26]
- Garvan Institute of Medical Research
- Avner Nahmani Pancreatic Cancer Research Foundation
- University of Glasgow
- Howat Foundation
- R.T. Hall Trust
- Petre Foundation
- Philip Hemstritch Foundation
- Gastroenterological Society of Australia (GESA)
- American Association for Cancer Research (AACR) Landon Foundation - INNOVATOR Award
- Royal Australasian College of Surgeons (RACS)
- Royal Australasian College of Physicians (RACP)
- Royal College of Pathologists of Australasia (RCPA)
- Italian Ministry of Research (Cancer Genome) [FIRB RBAP10AHJB]
- Associazione Italiana Ricerca Cancro [12182]
- Fondazione Italiana Malattie Pancreas - Ministero Salute [CUP_J33G13000210001]
- Wilhelm Sander Stiftung [2009.039.2]
- National Institutes of Health [P50 CA62924]
- Academy of Medical Sciences (AMS) [AMS-SGCL9-Jamieson] Funding Source: researchfish
- Cancer Research UK [17263] Funding Source: researchfish
- Wellcome Trust [103721/Z/14/Z] Funding Source: researchfish
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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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