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.

Authors	Scarpa, Aldo; Chang, David K.; Nones, Katia; Corbo, Vincenzo; Patch, Ann-Marie; Bailey, Peter; Lawlor, Rita T.; Johns, Amber L.; Miller, David K.; Mafficini, Andrea; Rusev, Borislav; Scardoni, Maria; Antonello, Davide; Barbi, Stefano; Sikora, Katarzyna O.; Cingarlini, Sara; Vicentini, Caterina; Mckay, Skye; Quinn, Michael C. J.; Bruxner, Timothy J. C.; Christ, Angelika N.; Harliwong, Ivon; Idrisoglu, Senel; McLean, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wilson, Peter J.; Anderson, Matthew J.; Fink, J. Lynn; Newell, Felicity; Waddell, Nick; Holmes, Oliver; Kazakoff, Stephen H.; Leonard, Conrad; Wood, Scott; Xu, Qinying; Nagaraj, Shivashankar Hiriyur; Amato, Eliana; Dalai, Irene; Bersanif, Samantha; Cataldo, Ivana; Tos, Angelo P. Dei; Capelli, Paola; Davi, Maria Vittoria; Landoni, Luca; Malpaga, Anna; Miotto, Marco; Whitehall, Vicki L. J.; Leggett, Barbara A.; Harris, Janelle L.; Harris, Jonathan; Jones, Marc D.; Humphris, Jeremy; Chantrill, Lorraine A.; Chin, Venessa; Nagrial, Adnan M.; Pajic, Marina; Scarlett, Christopher J.; Pinho, Andreia; Rooman, Ilse; Toon, Christopher; Wu, Jianmin; Pinese, Mark; Cowley, Mark; Barbour, Andrew; Mawson, Amanda; Humphrey, Emily S.; Colvin, Emily K.; Chou, Angela; Lovell, Jessica A.; Jamieson, Nigel B.; Duthie, Fraser; Gingras, Marie-Claude; Fisher, William E.; Dagg, Rebecca A.; Lau, Loretta M. S.; Lee, Michael; Pickett, Hilda A.; Reddel, Roger R.; Samra, Jaswinder S.; Kench, James G.; Merrett, Neil D.; Epari, Krishna; Nguyen, Nam Q.; Zeps, Nikolajs; Falconi, Massimo; Simbolo, Michele; Butturini, Giovanni; Van Buren, George, II; Partelli, Stefano; Fassan, Matteo; Khanna, Kum Kum; Gill, Anthony J.; Wheeler, David A.; Gibbs, Richard A.; Musgrove, Elizabeth A.; Bassi, Claudio; Tortora, Giampaolo; Pederzoli, Paolo; Pearson, John V.; Waddell, Nicola; Biankin, Andrew V.; Grimmond, Sean M.
Journal	NATURE
Pages	65-+
Volume	543
Date	1/03/2017
Grant ID	FIRB RBAP10AHJB
Funding Body	Italian Ministry of Research
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/nature21063