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Nature ; 543(7643): 65-71, 2017 03 02.
Article in English | MEDLINE | ID: mdl-28199314

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.


Subject(s)
Carcinoma, Neuroendocrine/genetics , Genome, Human/genetics , Genomics , Pancreatic Neoplasms/genetics , Base Sequence , Calmodulin-Binding Proteins/genetics , Chromatin Assembly and Disassembly/genetics , Chromosome Aberrations , DNA Copy Number Variations/genetics , DNA Glycosylases/genetics , DNA Mutational Analysis , DNA Repair/genetics , Female , Germ-Line Mutation/genetics , Humans , Male , RNA-Binding Protein EWS , RNA-Binding Proteins/genetics , TOR Serine-Threonine Kinases/metabolism , Telomere/genetics , Telomere/metabolism
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