| Literature DB >> 25719666 |
Nicola Waddell1, Marina Pajic2, Ann-Marie Patch3, David K Chang4, Karin S Kassahn3, Peter Bailey5, Amber L Johns6, David Miller3, Katia Nones3, Kelly Quek3, Michael C J Quinn3, Alan J Robertson3, Muhammad Z H Fadlullah3, Tim J C Bruxner3, Angelika N Christ3, Ivon Harliwong3, Senel Idrisoglu3, Suzanne Manning3, Craig Nourse5, Ehsan Nourbakhsh3, Shivangi Wani3, Peter J Wilson3, Emma Markham3, Nicole Cloonan1, Matthew J Anderson3, J Lynn Fink3, Oliver Holmes3, Stephen H Kazakoff3, Conrad Leonard3, Felicity Newell3, Barsha Poudel3, Sarah Song3, Darrin Taylor3, Nick Waddell3, Scott Wood3, Qinying Xu3, Jianmin Wu6, Mark Pinese6, Mark J Cowley6, Hong C Lee6, Marc D Jones7, Adnan M Nagrial6, Jeremy Humphris6, Lorraine A Chantrill6, Venessa Chin6, Angela M Steinmann6, Amanda Mawson6, Emily S Humphrey6, Emily K Colvin6, Angela Chou8, Christopher J Scarlett9, Andreia V Pinho6, Marc Giry-Laterriere6, Ilse Rooman6, Jaswinder S Samra10, James G Kench11, Jessica A Pettitt6, Neil D Merrett12, Christopher Toon6, Krishna Epari13, Nam Q Nguyen14, Andrew Barbour15, Nikolajs Zeps16, Nigel B Jamieson17, Janet S Graham18, Simone P Niclou19, Rolf Bjerkvig20, Robert Grützmann21, Daniela Aust21, Ralph H Hruban22, Anirban Maitra23, Christine A Iacobuzio-Donahue24, Christopher L Wolfgang25, Richard A Morgan22, Rita T Lawlor26, Vincenzo Corbo27, Claudio Bassi28, Massimo Falconi29, Giuseppe Zamboni30, Giampaolo Tortora31, Margaret A Tempero32, Anthony J Gill33, James R Eshleman22, Christian Pilarsky21, Aldo Scarpa26, Elizabeth A Musgrove34, John V Pearson1, Andrew V Biankin4, Sean M Grimmond5.
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.Entities:
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Year: 2015 PMID： 25719666 PMCID： PMC4523082 DOI： 10.1038/nature14169
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962