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Nature. 2017 Mar 2;543(7643):65-71. doi: 10.1038/nature21063. Epub 2017 Feb 15.

Whole-genome landscape of pancreatic neuroendocrine tumours.

Author information

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 and Hospital Trust of Verona, Verona 37134, Italy.
3
Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK.
4
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK.
5
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.
6
Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia.
7
South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia.
8
QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.
9
Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
10
Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
11
Medical Oncology, University and Hospital Trust of Verona, Verona, Italy.
12
Department of Pathology, General Hospital of Treviso, Department of Medicine, University of Padua, Italy.
13
Department of Medicine, Section of Endocrinology, University and Hospital Trust of Verona, Verona, Italy.
14
The University of Queensland, School of Medicine, Brisbane 4006, Australia.
15
Pathology Queensland, Brisbane 4006, Australia.
16
Royal Brisbane and Women's Hospital, Department of Gastroenterology and Hepatology, Brisbane 4006, Australia.
17
Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
18
School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia.
19
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Centre for Cancer Bioinformatics, Peking University Cancer Hospital &Institute, Beijing 100142, China.
20
Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia.
21
Department of Anatomical Pathology. St Vincent's Hospital, Sydney, New South Wales 2010, Australia.
22
Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK.
23
Department of Pathology, Queen Elizabeth University Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK.
24
Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
25
Michael E. DeBakey Department of Surgery and The Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA.
26
Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia.
27
Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales 2145, Australia.
28
Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia.
29
University of Sydney. Sydney, New South Wales 2006, Australia.
30
Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.
31
School of Medicine, Western Sydney University, Penrith, New South Wales 2175, Australia.
32
Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia.
33
Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.
34
School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands, Western Australia 6009, Australia.
35
St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia.
36
Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia 6008, Australia.
37
University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, 3010, Victoria, Australia.

Abstract

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

PMID:
28199314
DOI:
10.1038/nature21063
[Indexed for MEDLINE]

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