Hypermutation In Pancreatic Cancer

Jeremy L Humphris; Ann-Marie Patch; Katia Nones; Peter J Bailey; Amber L Johns; Skye McKay; David K Chang; David K Miller; Marina Pajic; Karin S Kassahn; Michael C J Quinn; Timothy J C Bruxner; Angelika N Christ; Ivon Harliwong; Senel Idrisoglu; Suzanne Manning; Craig Nourse; Ehsan Nourbakhsh; Andrew Stone; Peter J Wilson; Matthew Anderson; J Lynn Fink; Oliver Holmes; Stephen Kazakoff; Conrad Leonard; Felicity Newell; Nick Waddell; Scott Wood; Ronald S Mead; Qinying Xu; Jianmin Wu; Mark Pinese; Mark J Cowley; Marc D Jones; Adnan M Nagrial; Venessa T Chin; Lorraine A Chantrill; Amanda Mawson; Angela Chou; Christopher J Scarlett; Andreia V Pinho; Ilse Rooman; Marc Giry-Laterriere; Jaswinder S Samra; James G Kench; Neil D Merrett; Christopher W Toon; Krishna Epari; Nam Q Nguyen; Andrew Barbour; Nikolajs Zeps; Nigel B Jamieson; Colin J McKay; C Ross Carter; Euan J Dickson; Janet S Graham; Fraser Duthie; Karin Oien; Jane Hair; Jennifer P Morton; Owen J Sansom; Robert Grützmann; Ralph H Hruban; Anirban Maitra; Christine A Iacobuzio-Donahue; Richard D Schulick; Christopher L Wolfgang; Richard A Morgan; Rita T Lawlor; Borislav Rusev; Vincenzo Corbo; Roberto Salvia; Ivana Cataldo; Giampaolo Tortora; Margaret A Tempero; Australian Pancreatic Cancer Genome Initiative; Oliver Hofmann; James R Eshleman; Christian Pilarsky; Aldo Scarpa; Elizabeth A Musgrove; Anthony J Gill; John V Pearson; Sean M Grimmond; Nicola Waddell; Andrew V Biankin

doi:10.1053/j.gastro.2016.09.060

Hypermutation In Pancreatic Cancer

Gastroenterology. 2017 Jan;152(1):68-74.e2. doi: 10.1053/j.gastro.2016.09.060. Epub 2016 Nov 15.

Authors

Jeremy L Humphris¹, Ann-Marie Patch², Katia Nones², Peter J Bailey³, Amber L Johns¹, Skye McKay¹, David K Chang⁴, David K Miller⁵, Marina Pajic⁶, Karin S Kassahn⁷, Michael C J Quinn², Timothy J C Bruxner⁸, Angelika N Christ⁸, Ivon Harliwong⁸, Senel Idrisoglu⁸, Suzanne Manning⁸, Craig Nourse⁹, Ehsan Nourbakhsh⁸, Andrew Stone¹, Peter J Wilson⁸, Matthew Anderson⁸, J Lynn Fink⁸, Oliver Holmes², Stephen Kazakoff², Conrad Leonard², Felicity Newell², Nick Waddell⁸, Scott Wood², Ronald S Mead¹⁰, Qinying Xu², Jianmin Wu¹, Mark Pinese¹, Mark J Cowley⁶, Marc D Jones¹¹, Adnan M Nagrial¹, Venessa T Chin¹, Lorraine A Chantrill¹², Amanda Mawson¹, Angela Chou¹³, Christopher J Scarlett¹⁴, Andreia V Pinho¹, Ilse Rooman¹, Marc Giry-Laterriere¹, Jaswinder S Samra¹⁵, James G Kench¹⁶, Neil D Merrett¹⁷, Christopher W Toon¹, Krishna Epari¹⁸, Nam Q Nguyen¹⁹, Andrew Barbour²⁰, Nikolajs Zeps²¹, Nigel B Jamieson²², Colin J McKay²³, C Ross Carter²³, Euan J Dickson²³, Janet S Graham²⁴, Fraser Duthie²⁵, Karin Oien²⁵, Jane Hair²⁶, Jennifer P Morton²⁷, Owen J Sansom²⁷, Robert Grützmann²⁸, Ralph H Hruban²⁹, Anirban Maitra²⁹, Christine A Iacobuzio-Donahue²⁹, Richard D Schulick³⁰, Christopher L Wolfgang³⁰, Richard A Morgan²⁹, Rita T Lawlor³¹, Borislav Rusev³¹, Vincenzo Corbo³¹, Roberto Salvia³¹, Ivana Cataldo³¹, Giampaolo Tortora³², Margaret A Tempero³³; Australian Pancreatic Cancer Genome Initiative³⁴; Oliver Hofmann³⁵, James R Eshleman²⁹, Christian Pilarsky³⁶, Aldo Scarpa³¹, Elizabeth A Musgrove³⁷, Anthony J Gill³⁸, John V Pearson², Sean M Grimmond³⁹, Nicola Waddell⁴⁰, Andrew V Biankin⁴¹

Affiliations

¹ The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
² QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
³ Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
⁴ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom.
⁵ The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
⁶ The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia.
⁷ Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Genetic and Molecular Pathology, Adelaide, South Australia, Australia; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
⁸ Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
⁹ Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia.
¹⁰ The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; South Eastern Area Laboratory Services Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia; Sonic Genetics, Douglass Hanly Moir Pathology, New South Wales, Australia.
¹¹ The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
¹² The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales, Australia.
¹³ The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Department of Anatomical Pathology, SydPath, St Vincent's Hospital, New South Wales, Australia.
¹⁴ The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia.
¹⁵ Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia.
¹⁶ The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
¹⁷ Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; School of Medicine, Western Sydney University, Penrith, New South Wales, Australia.
¹⁸ Department of Surgery, Fiona Stanley Hospital, Murdoch, Washington.
¹⁹ Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia.
²⁰ Department of Surgery, Princess Alexandra Hospital, Woollongabba, Queensland, Australia.
²¹ School of Surgery, University of Western Australia, Australia and St John of God Pathology, Subiaco, Washington.
²² Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom.
²³ West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom.
²⁴ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
²⁵ Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde National Health Service, Glasgow, United Kingdom.
²⁶ Greater Glasgow and Clyde Bio-repository, Pathology Department, Queen Elizabeth University Hospital, Glasgow, United Kingdom.
²⁷ Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute for Cancer Science, University of Glasgow, Glasgow, United Kingdom.
²⁸ Universitätsklinikum Erlangen, Erlangen, Germany.
²⁹ Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland.
³⁰ Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland.
³¹ ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
³² Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.
³³ Division of Hematology and Oncology, University of California, San Francisco, California.
³⁴ Australian Pancreatic Cancer Genome Initiative.
³⁵ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
³⁶ Universitätsklinikum Erlangen, Department of Surgery, University of Erlangen-Nueremberg, Germany.
³⁷ The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia.
³⁸ The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia.
³⁹ Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia.
⁴⁰ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. Electronic address: nic.waddell@qimrberghofer.edu.au.
⁴¹ Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. Electronic address: andrew.biankin@glasgow.ac.uk.

PMID: 27856273
DOI: 10.1053/j.gastro.2016.09.060

Abstract

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

Keywords: Cancer Genetics; Pancreatic Adenocarcinoma; Sequencing; Somatic Rearrangement.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adult
Aged
Aged, 80 and over
Carcinoma, Pancreatic Ductal / genetics*
DNA Mismatch Repair / genetics*
DNA Mutational Analysis
Female
Genome
Humans
Male
Middle Aged
MutL Protein Homolog 1 / genetics
MutS Homolog 2 Protein / genetics
Mutation*
Pancreatic Neoplasms / genetics*
Proto-Oncogene Proteins p21(ras) / genetics
Transcriptome*

Substances

KRAS protein, human
MLH1 protein, human
MSH2 protein, human
MutL Protein Homolog 1
MutS Homolog 2 Protein
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding