Whole-genome landscape of pancreatic neuroendocrine tumours

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

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.