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Nature Research, Nature, 7643(543), p. 65-71, 2017

DOI: 10.1038/nature21063

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Whole-genome landscape of pancreatic neuroendocrine tumours

Journal article published in 2017 by Aldo Scarpa, David K. Chang, Katia Nones, Vincenzo Corbo, Ann-Marie Patch, Peter Bailey, Rita T. Lawlor ORCID, Amber L. Johns, David K. Miller, Chang Dk, Andrea Mafficini, Borislav Rusev, Katarzyna O. Sikora, Maria Scardoni, Davide Antonello and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Data provided by SHERPA/RoMEO

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.