Whole genomes redefine the mutational landscape of pancreatic cancer

Article


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, ..., Grimmond, Sean M.. 2015. "Whole genomes redefine the mutational landscape of pancreatic cancer." Nature. 518 (7540), pp. 495-501. https://doi.org/10.1038/nature14169
Article Title

Whole genomes redefine the mutational landscape of pancreatic cancer

ERA Journal ID17479
Article CategoryArticle
AuthorsWaddell, Nicola (Author), Pajic, Marina (Author), Patch, Ann-Marie (Author), Chang, David K. (Author), Kassahn, Karin S. (Author), Bailey, Peter (Author), Johns, Amber L. (Author), Miller, David (Author), Nones, Katia (Author), Quek, Kelly (Author), Quinn, Michael C. J. (Author), Robertson, Alan J. (Author), Fadlullah, Muhammad Z. H. (Author), Bruxner, Tim J. C. (Author), Christ, Angelika N. (Author), Harliwong, Ivon (Author), Idrisoglu, Senel (Author), Manning, Suzanne (Author), Nourse, Craig (Author), Nourbakhsh, Ehsan (Author), Wani, Shivangi (Author), Wilson, Peter J. (Author), Markham, Emma (Author), Cloonan, Nicole (Author), Anderson, Matthew J. (Author), Fink, J. Lynn (Author), Holmes, Oliver (Author), Kazakoff, Stephen H. (Author), Leonard, Conrad (Author), Newell, Felicity (Author), Poudel, Barsha (Author), Song, Sarah (Author), Taylor, Darrin (Author), Waddell, Nick (Author), Wood, Scott (Author), Xu, Qinying (Author), Wu, Jianmin (Author), Pinese, Mark (Author), Cowley, Mark J. (Author), Lee, Hong C. (Author), Jones, Marc D. (Author), Nagrial, Adnan M. (Author), Humphris, Jeremy (Author), Chantrill, Lorraine A. (Author), Chin, Venessa (Author), Steinmann, Angela M. (Author), Mawson, Amanda (Author), Humphrey, Emily S. (Author), Colvin, Emily K. (Author), Chou, Angela (Author), Scarlett, Christopher J. (Author), Pinho, Andreia V. (Author), Giry-Laterriere, Marc (Author), Rooman, Ilse (Author), Samra, Jaswinder S. (Author), Kench, James G. (Author), Pettitt, Jessica A. (Author), Merrett, Neil D. (Author), Toon, Christopher (Author), Epari, Krishna (Author), Nguyen, Nam Q. (Author), Barbour, Andrew (Author), Zeps, Nikolajs (Author), Jamieson, Nigel B. (Author), Graham, Janet S. (Author), Niclou, Simone P. (Author), Bjerkvig, Rolf (Author), Grutzmann, Robert (Author), Aust, Daniela (Author), Hruban, Ralph H. (Author), Maitra, Anirban (Author), Iacobuzio-Donahue, Christine A. (Author), Wolfgang, Christopher L. (Author), Morgan, Richard A. (Author), Lawlor, Rita T. (Author), Corbo, Vincenzo (Author), Bassi, Claudio (Author), Falconi, Massimo (Author), Zamboni, Giuseppe (Author), Tortora, Giampaolo (Author), Tempero, Margaret A. (Author), Gill, Anthony J. (Author), Eshleman, James R. (Author), Pilarsky, Christian (Author), Scarpa, Aldo (Author), Musgrove, Elizabeth A. (Author), Pearson, John V. (Author), Biankin, Andrew V. (Author) and Grimmond, Sean M. (Author)
Journal TitleNature
Journal Citation518 (7540), pp. 495-501
Number of Pages7
Year2015
PublisherNature Publishing Group
Place of PublicationUnited Kingdom
ISSN0028-0836
0090-0028
0300-8746
1476-4687
Digital Object Identifier (DOI)https://doi.org/10.1038/nature14169
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.

Keywordspancreatic cancer; whole-genome sequencing; copy number variation
ANZSRC Field of Research 2020321103. Cancer genetics
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Byline AffiliationsUniversity of Queensland
University of New South Wales
Department of Health, New South Wales
Department of Health, Western Australia
Department of Health, South Australia
Department of Health, Queensland
University of Western Australia
University of Glasgow, United Kingdom
Norlux Neuro-Oncology Laboratory, Luxembourg
University of Bergen, Norway
Dresden University of Technology, Germany
Johns Hopkins University, United States
University of Texas at Austin, United States
Memorial Sloan Kettering Cancer Center, United States
University and Hospital Trust of Verona, Italy
University of Verona, Italy
University of California, United States
John Hopkins University, United States
Institution of OriginUniversity of Southern Queensland
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