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Whole-genome landscape of pancreatic neuroendocrine tumours

2017; Nature Portfolio; Volume: 543; Issue: 7643 Linguagem: Inglês

10.1038/nature21063

1476-4687

Aldo Scarpa, David K. Chang, Kátia Nones, Vincenzo Corbo, Ann‐Marie Patch, Peter J. Bailey, Rita T. Lawlor, Amber L. Johns, David K. Miller, Andrea Mafficini, Borislav C. Rusev, Maria Scardoni, Davide Antonello, Stefano Barbi, Katarzyna Sikora, Sara Cingarlini, Caterina Vicentini, Skye McKay, Michael C. 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 M. Waddell, Oliver Holmes, Stephen H. Kazakoff, Conrad Leonard, Scott Wood, Qinying Xu, Shivashankar H. Nagaraj, Eliana Amato, Irene Dalai, Samantha Bersani, Ivana Cataldo, Angelo Paolo Dei Tos, Paola Capelli, Maria Vittoria Davì, Luca Landoni, Anna Malpaga, Marco Miotto, Vicki Whitehall, Barbara Leggett, Janelle L. Harris, Jonathan M. Harris, Marc D. Jones, Jeremy L. Humphris, Lorraine A. Chantrill, Venessa Chin, Adnan Nagrial, Marina Pajic, Christopher J. Scarlett, Andreia V. Pinho, Ilse Rooman, Christopher W. Toon, Jianmin Wu, Mark Pinese, Mark J. Cowley, Andrew P. Barbour, Amanda Mawson, Emily S. Humphrey, Emily K. Colvin, Angela Chou, Jessica A. Lovell, Nigel B. Jamieson, Fraser R. 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,

Lung Cancer Research Studies

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. The genomes of 102 primary pancreatic neuroendocrine tumours have been sequenced, revealing mutations in genes with functions such as chromatin remodelling, DNA damage repair, mTOR activation and telomere maintenance, and a greater-than-expected contribution from germ line mutations. Pancreatic neuroendocrine tumours (PanNETs) are the second most common epithelial neoplasm of the pancreas. Aldo Scarpa, Sean Grimmond and colleagues report whole-genome sequencing of 102 primary PanNETs and present analysis of their mutational signatures as part of the International Cancer Genome Consortium. They find frequent mutations in genes with functions that include chromatin remodelling, DNA damage repair, activation of mTOR signalling, and telomere maintenance. They also identify mutational signatures, including one resulting from inactivation of the DNA repair gene MUTYH, and report a larger than expected germline contribution to PanNET development.