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Nature. 2015 Feb 26;518(7540):495-501. doi: 10.1038/nature14169.

Whole genomes redefine the mutational landscape of pancreatic cancer.

Collaborators (157)

Biankin AV, Johns AL, Mawson A, Chang DK, Scarlett CJ, Brancato MA, Rowe SJ, Simpson SH, Martyn-Smith M, Thomas MT, Chantrill LA, Chin VT, Chou A, Cowley MJ, Humphris JL, Jones MD, Mead RS, Nagrial AM, Pajic M, Pettit J, Pinese M, Rooman I, Wu J, Tao J, DiPietro R, Watson C, Steinmann A, Ching Lee H, Wong R, Pinho AV, Giry-Laterriere M, Daly RJ, Musgrove EA, Sutherland RL, Grimmond SM, Waddell N, Kassahn KS, Miller DK, Wilson PJ, Patch AM, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu C, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Newell F, Pearson JV, Bailey P, Quinn M, Nagaraj S, Kazakoff S, Waddell N, Krisnan K, Quek K, Wood D, Fadlullah MZ, Samra JS, Gill AJ, Pavlakis N, Guminski A, Toon C, Asghari R, Merrett ND, Pavey D, Das A, Cosman PH, Ismail K, O'Connnor C, Lam VW, McLeod D, Pleass HC, Richardson A, James V, Kench JG, Cooper CL, Joseph D, Sandroussi C, Crawford M, Gallagher J, Texler M, Forest C, Laycock A, Epari KP, Ballal M, Fletcher DR, Mukhedkar S, Spry NA, DeBoer B, Chai M, Zeps N, Beilin M, Feeney K, Nguyen NQ, Ruszkiewicz AR, Worthley C, Tan CP, Debrencini T, Chen J, Brooke-Smith ME, Papangelis V, Tang H, Barbour AP, Clouston AD, Martin P, O'Rourke TJ, Chiang A, Fawcett JW, Slater K, Yeung S, Hatzifotis M, Hodgkinson P, Christophi C, Nikfarjam M, Mountain A, Eshleman JR, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Hodgin M, Scarpa A, Lawlor RT, Beghelli S, Corbo V, Scardoni M, Bassi C, Tempero MA, Biankin AV, Grimmond SM, Chang DK, Musgrove EA, Jones MD, Nourse C, Jamieson NB, Graham JS, Biankin AV, Chang DK, Jamieson NB, Graham JS, Oien K, Hair J.

Author information

1
1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia [2] QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.
2
1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2010, Australia.
3
Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
4
1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia [3] South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia [4] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
5
1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia [2] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
6
The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.
7
1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
8
1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] Department of Anatomical Pathology, St Vincent's Hospital, Sydney, New South Wales 2010, Australia.
9
1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia.
10
1] Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia [2] University of Sydney, Sydney, New South Wales 2006, Australia.
11
1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] University of Sydney, Sydney, New South Wales 2006, Australia [3] Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.
12
1] Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia [2] School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia.
13
Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia.
14
Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.
15
Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia.
16
1] School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands 6009, Australia [2] St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia [3] Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia 6008, Australia.
17
1] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK [2] Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK [3] West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK.
18
1] Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK [2] Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK.
19
Norlux Neuro-Oncology Laboratory, CRP-Santé Luxembourg, 84 Val Fleuri, L-1526, Luxembourg.
20
Norlux Neuro-Oncology, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5019 Bergen, Norway.
21
Departments of Surgery and Pathology, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
22
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
23
Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston Texas 77030, USA.
24
The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
25
Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
26
1] ARC-NET Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy [2] Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy.
27
ARC-NET Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.
28
Department of Surgery and Oncology, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
29
1] Department of Surgery and Oncology, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy [2] Departments of Surgery and Pathology, Ospedale Sacro Cuore Don Calabria Negrar, Verona 37024, Italy.
30
1] Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy [2] Departments of Surgery and Pathology, Ospedale Sacro Cuore Don Calabria Negrar, Verona 37024, Italy.
31
Department of Oncology, University and Hospital Trust of Verona, Verona 37134, Italy.
32
Division of Hematology and Oncology, University of California, San Francisco, California 94122, USA.
33
1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] University of Sydney, Sydney, New South Wales 2006, Australia.
34
Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.

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.

PMID:
25719666
PMCID:
PMC4523082
DOI:
10.1038/nature14169
[Indexed for MEDLINE]
Free PMC Article
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