Whole genomes redefine the mutational landscape of pancreatic cancer
Nicola Waddell, Marina Pajic, Ann-Marie Patch, David K Chang, Karin S Kassahn, Peter Bailey, Amber L Johns, David Miller, Katia Nones, Kelly Quek, Michael C J Quinn, Alan J Robertson, Muhammad Z H Fadlullah, Tim J C Bruxner, Angelika N Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan Nourbakhsh, Shivangi Wani, Peter J Wilson, Emma Markham, Nicole Cloonan, Matthew J Anderson, J Lynn Fink, Oliver Holmes, Stephen H Kazakoff, Conrad Leonard, Felicity Newell, Barsha Poudel, Sarah Song, Darrin Taylor, Nick Waddell, Scott Wood, Qinying Xu, Jianmin Wu, Mark Pinese, Mark J Cowley, Hong C Lee, Marc D Jones, Adnan M Nagrial, Jeremy Humphris, Lorraine A Chantrill, Venessa Chin, Angela M Steinmann, Amanda Mawson, Emily S Humphrey, Emily K Colvin, Angela Chou, Christopher J Scarlett, Andreia V Pinho, Marc Giry-Laterriere, Ilse Rooman, Jaswinder S Samra, James G Kench, Jessica A Pettitt, Neil D Merrett, Christopher Toon, Krishna Epari, Nam Q Nguyen, Andrew Barbour, Nikolajs Zeps, Nigel B Jamieson, Janet S Graham, Simone P Niclou, Rolf Bjerkvig, Robert Grützmann, Daniela Aust, Ralph H Hruban, Anirban Maitra, Christine A Iacobuzio-Donahue, Christopher L Wolfgang, Richard A Morgan, Rita T Lawlor, Vincenzo Corbo, Claudio Bassi, Massimo Falconi, Giuseppe Zamboni, Giampaolo Tortora, Margaret A Tempero, Australian Pancreatic Cancer Genome Initiative, Anthony J Gill, James R Eshleman, Christian Pilarsky, Aldo Scarpa, Elizabeth A Musgrove, John V Pearson, Andrew V Biankin, Sean M Grimmond, Andrew V Biankin, Amber L Johns, Amanda Mawson, David K Chang, Christopher J Scarlett, Mary-Anne L Brancato, Sarah J Rowe, Skye H Simpson, Mona Martyn-Smith, Michelle T Thomas, Lorraine A Chantrill, Venessa T Chin, Angela Chou, Mark J Cowley, Jeremy L Humphris, Marc D Jones, R Scott Mead, Adnan M Nagrial, Marina Pajic, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V Pinho, Marc Giry-Laterriere, Roger J Daly, Elizabeth A Musgrove, Robert L Sutherland, Sean M Grimmond, Nicola Waddell, Karin S Kassahn, David K Miller, Peter J Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, J Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V Pearson, Peter Bailey, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Muhammad Z H Fadlullah, Jaswinder S Samra, Anthony J Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D Merrett, Darren Pavey, Amitabha Das, Peter H Cosman, Kasim Ismail, Chelsie O'Connnor, Vincent W Lam, Duncan McLeod, Henry C Pleass, Arthur Richardson, Virginia James, James G Kench, Caroline L Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P Epari, Mo Ballal, David R Fletcher, Sanjay Mukhedkar, Nigel A Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q Nguyen, Andrew R Ruszkiewicz, Chris Worthley, Chuan P Tan, Tamara Debrencini, John Chen, Mark E Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P Barbour, Andrew D Clouston, Patrick Martin, Thomas J O'Rourke, Amy Chiang, Jonathan W Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, James R Eshleman, Ralph H Hruban, Anirban Maitra, Christine A Iacobuzio-Donahue, Richard D Schulick, Christopher L Wolfgang, Richard A Morgan, Mary Hodgin, Aldo Scarpa, Rita T Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A Tempero, Andrew V Biankin, Sean M Grimmond, David K Chang, Elizabeth A Musgrove, Marc D Jones, Craig Nourse, Nigel B Jamieson, Janet S Graham, Andrew V Biankin, David K Chang, Nigel B Jamieson, Janet S Graham, Karen Oien, Jane Hair, Nicola Waddell, Marina Pajic, Ann-Marie Patch, David K Chang, Karin S Kassahn, Peter Bailey, Amber L Johns, David Miller, Katia Nones, Kelly Quek, Michael C J Quinn, Alan J Robertson, Muhammad Z H Fadlullah, Tim J C Bruxner, Angelika N Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan Nourbakhsh, Shivangi Wani, Peter J Wilson, Emma Markham, Nicole Cloonan, Matthew J Anderson, J Lynn Fink, Oliver Holmes, Stephen H Kazakoff, Conrad Leonard, Felicity Newell, Barsha Poudel, Sarah Song, Darrin Taylor, Nick Waddell, Scott Wood, Qinying Xu, Jianmin Wu, Mark Pinese, Mark J Cowley, Hong C Lee, Marc D Jones, Adnan M Nagrial, Jeremy Humphris, Lorraine A Chantrill, Venessa Chin, Angela M Steinmann, Amanda Mawson, Emily S Humphrey, Emily K Colvin, Angela Chou, Christopher J Scarlett, Andreia V Pinho, Marc Giry-Laterriere, Ilse Rooman, Jaswinder S Samra, James G Kench, Jessica A Pettitt, Neil D Merrett, Christopher Toon, Krishna Epari, Nam Q Nguyen, Andrew Barbour, Nikolajs Zeps, Nigel B Jamieson, Janet S Graham, Simone P Niclou, Rolf Bjerkvig, Robert Grützmann, Daniela Aust, Ralph H Hruban, Anirban Maitra, Christine A Iacobuzio-Donahue, Christopher L Wolfgang, Richard A Morgan, Rita T Lawlor, Vincenzo Corbo, Claudio Bassi, Massimo Falconi, Giuseppe Zamboni, Giampaolo Tortora, Margaret A Tempero, Australian Pancreatic Cancer Genome Initiative, Anthony J Gill, James R Eshleman, Christian Pilarsky, Aldo Scarpa, Elizabeth A Musgrove, John V Pearson, Andrew V Biankin, Sean M Grimmond, Andrew V Biankin, Amber L Johns, Amanda Mawson, David K Chang, Christopher J Scarlett, Mary-Anne L Brancato, Sarah J Rowe, Skye H Simpson, Mona Martyn-Smith, Michelle T Thomas, Lorraine A Chantrill, Venessa T Chin, Angela Chou, Mark J Cowley, Jeremy L Humphris, Marc D Jones, R Scott Mead, Adnan M Nagrial, Marina Pajic, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V Pinho, Marc Giry-Laterriere, Roger J Daly, Elizabeth A Musgrove, Robert L Sutherland, Sean M Grimmond, Nicola Waddell, Karin S Kassahn, David K Miller, Peter J Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, J Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V Pearson, Peter Bailey, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Muhammad Z H Fadlullah, Jaswinder S Samra, Anthony J Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D Merrett, Darren Pavey, Amitabha Das, Peter H Cosman, Kasim Ismail, Chelsie O'Connnor, Vincent W Lam, Duncan McLeod, Henry C Pleass, Arthur Richardson, Virginia James, James G Kench, Caroline L Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P Epari, Mo Ballal, David R Fletcher, Sanjay Mukhedkar, Nigel A Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q Nguyen, Andrew R Ruszkiewicz, Chris Worthley, Chuan P Tan, Tamara Debrencini, John Chen, Mark E Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P Barbour, Andrew D Clouston, Patrick Martin, Thomas J O'Rourke, Amy Chiang, Jonathan W Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, James R Eshleman, Ralph H Hruban, Anirban Maitra, Christine A Iacobuzio-Donahue, Richard D Schulick, Christopher L Wolfgang, Richard A Morgan, Mary Hodgin, Aldo Scarpa, Rita T Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A Tempero, Andrew V Biankin, Sean M Grimmond, David K Chang, Elizabeth A Musgrove, Marc D Jones, Craig Nourse, Nigel B Jamieson, Janet S Graham, Andrew V Biankin, David K Chang, Nigel B Jamieson, Janet S Graham, Karen Oien, Jane Hair
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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Source: PubMed