Whole genomes redefine the mutational landscape of pancreatic cancer

Waddell, Nicola, Pajic, Marina, Patch, Anne-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, Nourbakhsh, Ehsan, Wani, Shivangi, Wilson, Peter J, Markham, Emma, Cloonan, Nicole, Anderson, Matthew J, Fink, J. Lynn, Holmes, Oliver, Kazakoff, Stephen H, Leonard, Conrad, Newell, Felicity, Poudel, Barsha, Song, Sarah, Taylor, Darrin, Waddell, Nick, Wood, Scott, Xu, Qinying, Wu, Jianmin, Pinese, Mark, Cowley, Mark J, Lee, Hong C, Jones, Marc D, Nagrial, Adnan M, Humphris, Jeremy, Chantrill, Lorraine A, Chin, Venessa, Steinmann, Angela M, Mawson, Amanda, Humphrey, Emily S, Colvin, Emily K, Chou, Angela, Scarlett, Christopher J, Pinho, Andreia V, Giry-Laterriere, Marc, Rooman, Ilse, Samra, Jaswinder S, Kench, James G, Pettitt, Jessica A, Merrett, Neil D, Toon, Christopher, Epari, Krishna, Nguyen, Nam Q, Barbour, Andrew, Zeps, Nikolajs, Jamieson, Nigel B, Graham, Janet S, Niclou, Simone P, Bjerkvig, Rolf, Grutzmann, Robert, Aust, Daniela, Hruban, Ralph H, Maitra, Anirban, Iacobuzio-Donahue, Christine A, Wolfgang, Christopher L, Morgan, Richard A, Lawlor, Rita T, Corbo, Vincenzo, Bassi, Claudio, Falconi, Massimo, Zamboni, Giuseppe, Tortora, Giampaolo, Tempero, Margaret A, Gill, Anthony J, Eshleman, James R, Pilarsky, Christian, Scarpa, Aldo, Musgrove, Elizabeth A, Pearson, John V, Biankin, Andrew V and Grimmond, Sean M (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature, 518 7540: 495-501. doi:10.1038/nature14169


Author Waddell, Nicola
Pajic, Marina
Patch, Anne-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
Nourbakhsh, Ehsan
Wani, Shivangi
Wilson, Peter J
Markham, Emma
Cloonan, Nicole
Anderson, Matthew J
Fink, J. Lynn
Holmes, Oliver
Kazakoff, Stephen H
Leonard, Conrad
Newell, Felicity
Poudel, Barsha
Song, Sarah
Taylor, Darrin
Waddell, Nick
Wood, Scott
Xu, Qinying
Wu, Jianmin
Pinese, Mark
Cowley, Mark J
Lee, Hong C
Jones, Marc D
Nagrial, Adnan M
Humphris, Jeremy
Chantrill, Lorraine A
Chin, Venessa
Steinmann, Angela M
Mawson, Amanda
Humphrey, Emily S
Colvin, Emily K
Chou, Angela
Scarlett, Christopher J
Pinho, Andreia V
Giry-Laterriere, Marc
Rooman, Ilse
Samra, Jaswinder S
Kench, James G
Pettitt, Jessica A
Merrett, Neil D
Toon, Christopher
Epari, Krishna
Nguyen, Nam Q
Barbour, Andrew
Zeps, Nikolajs
Jamieson, Nigel B
Graham, Janet S
Niclou, Simone P
Bjerkvig, Rolf
Grutzmann, Robert
Aust, Daniela
Hruban, Ralph H
Maitra, Anirban
Iacobuzio-Donahue, Christine A
Wolfgang, Christopher L
Morgan, Richard A
Lawlor, Rita T
Corbo, Vincenzo
Bassi, Claudio
Falconi, Massimo
Zamboni, Giuseppe
Tortora, Giampaolo
Tempero, Margaret A
Gill, Anthony J
Eshleman, James R
Pilarsky, Christian
Scarpa, Aldo
Musgrove, Elizabeth A
Pearson, John V
Biankin, Andrew V
Grimmond, Sean M
Title Whole genomes redefine the mutational landscape of pancreatic cancer
Journal name Nature   Check publisher's open access policy
ISSN 1476-4687
0028-0836
Publication date 2015-02-25
Year available 2015
Sub-type Article (original research)
DOI 10.1038/nature14169
Open Access Status DOI
Volume 518
Issue 7540
Start page 495
End page 501
Total pages 7
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1000 General
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.
Formatted 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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID P50 CA062924
C596/A18076
P30 CA006973
103721
P50 CA62924
C29717/A17263
Institutional Status UQ

 
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