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.

Whole-genome landscape of pancreatic neuroendocrine tumours

Scarpa, Aldo;Corbo, Vincenzo
Conceptualization
;
Lawlor, Rita T;Mafficini, Andrea;Rusev, Borislav;Scardoni, Maria;Antonello, Davide;Barbi, Stefano;Cingarlini, Sara;Vicentini, Caterina;Amato, Eliana;Dalai, Irene;Bersani, Samantha;Cataldo, Ivana;Capelli, Paola;Davì, Maria Vittoria;Landoni, Luca;Malpaga, Anna;Miotto, Marco;Falconi, Massimo;Simbolo, Michele;Butturini, Giovanni;Partelli, Stefano;Fassan, Matteo;Bassi, Claudio;Tortora, Giampaolo;Pederzoli, Paolo;
2017

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.
pancreatic neuroendocrine tumours (PanNETs)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/958472
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