Whole genomes redefine the mutational landscape of pancreatic cancer

Waddell, Nicola and Pajic, Marina and Patch, Ann-Marie and Chang, David K. and Kassahn, Karin S. and Bailey, Peter and Johns, Amber L. and Miller, David and Nones, Katia and Quek, Kelly and Quinn, Michael C. J. and Robertson, Alan J. and Fadlullah, Muhammad Z. H. and Bruxner, Tim J. C. and Christ, Angelika N. and Harliwong, Ivon and Idrisoglu, Senel and Manning, Suzanne and Nourse, Craig and Nourbakhsh, Ehsan and Wani, Shivangi and Wilson, Peter J. and Markham, Emma and Cloonan, Nicole and Anderson, Matthew J. and Fink, J. Lynn and Holmes, Oliver and Kazakoff, Stephen H. and Leonard, Conrad and Newell, Felicity and Poudel, Barsha and Song, Sarah and Taylor, Darrin and Waddell, Nick and Wood, Scott and Xu, Qinying and Wu, Jianmin and Pinese, Mark and Cowley, Mark J. and Lee, Hong C. and Jones, Marc D. and Nagrial, Adnan M. and Humphris, Jeremy and Chantrill, Lorraine A. and Chin, Venessa and Steinmann, Angela M. and Mawson, Amanda and Humphrey, Emily S. and Colvin, Emily K. and Chou, Angela and Scarlett, Christopher J. and Pinho, Andreia V. and Giry-Laterriere, Marc and Rooman, Ilse and Samra, Jaswinder S. and Kench, James G. and Pettitt, Jessica A. and Merrett, Neil D. and Toon, Christopher and Epari, Krishna and Nguyen, Nam Q. and Barbour, Andrew and Zeps, Nikolajs and Jamieson, Nigel B. and Graham, Janet S. and Niclou, Simone P. and Bjerkvig, Rolf and Grutzmann, Robert and Aust, Daniela and Hruban, Ralph H. and Maitra, Anirban and Iacobuzio-Donahue, Christine A. and Wolfgang, Christopher L. and Morgan, Richard A. and Lawlor, Rita T. and Corbo, Vincenzo and Bassi, Claudio and Falconi, Massimo and Zamboni, Giuseppe and Tortora, Giampaolo and Tempero, Margaret A. and Australian Pancreatic Cancer Genome Initiative, and Gill, Anthony J. and Eshleman, James R. and Pilarsky, Christian and Scarpa, Aldo and Musgrove, Elizabeth A. and Pearson, John V. and Biankin, Andrew V. and Grimmond, Sean M. (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature, 518 (7540). pp. 495-501. ISSN 0028-0836

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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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: Files associated with this item cannot be displayed due to copyright restrictions.
Faculty / Department / School: No Faculty
Date Deposited: 29 Aug 2017 05:38
Last Modified: 29 Aug 2017 05:38
Uncontrolled Keywords: pancreatic cancer; whole-genome sequencing; copy number variation
Fields of Research : 11 Medical and Health Sciences > 1112 Oncology and Carcinogenesis > 111203 Cancer Genetics
Identification Number or DOI: 10.1038/nature14169
URI: http://eprints.usq.edu.au/id/eprint/32658

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