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Whole-genome landscape of pancreatic neuroendocrine tumours

Journal Contribution - Journal Article

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.

Journal: Nature
ISSN: 0028-0836
Issue: 7643
Volume: 543
Pages: 65-71
Number of pages: 7
Publication year:2017
Keywords:Base Sequence, Calmodulin-Binding Proteins/genetics, Carcinoma, Neuroendocrine/genetics, Chromatin Assembly and Disassembly/genetics, Chromosome Aberrations, DNA Copy Number Variations/genetics, DNA Glycosylases/genetics, DNA Mutational Analysis, DNA Repair/genetics, Female, Genome, Human/genetics, Genomics, Germ-Line Mutation/genetics, Humans, Male, Pancreatic Neoplasms/genetics, RNA-Binding Protein EWS, RNA-Binding Proteins/genetics, TOR Serine-Threonine Kinases/metabolism, Telomere/genetics