Whole-genome landscape of pancreatic neuroendocrine tumours

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Telomere / metabolism


  • Calmodulin-Binding Proteins
  • EWSR1 protein, human
  • RNA-Binding Protein EWS
  • RNA-Binding Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • DNA Glycosylases
  • mutY adenine glycosylase