Journal
NATURE
Volume 543, Issue 7643, Pages 65-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature21063
Keywords
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Categories
Funding
- Italian Ministry of Research [FIRB RBAP10AHJB]
- Associazione Italiana Ricerca Cancro (AIRC) [12182]
- Fondazione Italiana Malattie Pancreas - Ministero Salute [CUP_J33G13000210001]
- National Health and Medical Research Council of Australia (NHMRC) [631701, 535903, CDF 1112113, PRF 1025427, SRF 455857]
- Queensland State Government Smart State National and International Research Alliances Program (NIRAP)
- Institute for Molecular Bioscience/University of Queensland
- Royal Australasian College of Physicians
- Sidney Catalyst
- NHMRC
- Pancare Australia
- Australian Government: Department of Innovation, Industry, Science and Research (DIISR)
- Australian Cancer Research Foundation (ACRF)
- Cancer Council NSW [SRP06-01, SRP11-01.ICGC]
- Cancer Institute NSW [10/ECF/2-26, 06/ECF/1-24, 09/CDF/2-40, 07/CDF/1-03, 10/CRF/1-01, 08/RSA/1-15, 07/CDF/1-28, 10/CDF/2-26, 10/FRL/2-03, 06/RSA/1-05, 09/RIG/1-02, 10/TPG/1-04, 11/REG/1-10, 11/CDF/3-26]
- Garvan Institute of Medical Research
- Avner Nahmani Pancreatic Cancer Research Foundation
- R.T. Hall Trust
- Petre Foundation
- Philip Hemstritch Foundation
- Gastroenterological Society of Australia (GESA Senior Research Fellowship)
- Royal Australasian College of Surgeons (RACS)
- Royal Australasian College of Physicians (RACP)
- Royal College of Pathologists of Australasia (RCPA)
- QIMR Berghofer Medical Research
- Keith Boden Fellowship
- NHGRI [U54 HG003273]
- CPRIT grant [RP101353-P7]
- Wellcome Trust [103721/Z/14/Z]
- CRUK Programme [C29717/A17263, C29717/A18484]
- CRUK Glasgow Centre [C596/A18076]
- CRUK Clinical Training Award [C596/A20921]
- Pancreatic Cancer UK Future Research Leaders Fund
- Howat Foundation
- University of Glasgow
- Academy of Medical Sciences (AMS) [AMS-SGCL9-Jamieson] Funding Source: researchfish
- Cancer Research UK [17263, 23526, 22533] Funding Source: researchfish
- Medical Research Council [MR/N005813/1] Funding Source: researchfish
- Pancreatic Cancer UK [RIF2015_A06_Jamieson, FLF2015_04_Glasgow] Funding Source: researchfish
- Wellcome Trust [103721/Z/14/Z] Funding Source: researchfish
- MRC [MR/N005813/1] Funding Source: UKRI
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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.
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