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Whole-genome landscape of pancreatic neuroendocrine tumours


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.

Type Journal
ISBN 1476-4687 (Electronic) 0028-0836 (Linking)
Authors Scarpa, A.; Chang, D. K.; Nones, K.; Corbo, V.; Patch, A. M.; Bailey, P.; Lawlor, R. T.; Johns, A. L.; Miller, D. K.; Mafficini, A.; Rusev, B.; Scardoni, M.; Antonello, D.; Barbi, S.; Sikora, K. O.; Cingarlini, S.; Vicentini, C.; McKay, S.; Quinn, M. C.; Bruxner, T. J.; Christ, A. N.; Harliwong, I.; Idrisoglu, S.; McLean, S.; Nourse, C.; Nourbakhsh, E.; Wilson, P. J.; Anderson, M. J.; Fink, J. L.; Newell, F.; Waddell, N.; Holmes, O.; Kazakoff, S. H.; Leonard, C.; Wood, S.; Xu, Q.; Nagaraj, S. H.; Amato, E.; Dalai, I.; Bersani, S.; Cataldo, I.; Dei Tos, A. P.; Capelli, P.; Davi, M. V.; Landoni, L.; Malpaga, A.; Miotto, M.; Whitehall, V. L.; Leggett, B. A.; Harris, J. L.; Harris, J.; Jones, M. D.; Humphris, J.; Chantrill, L. A.; Chin, V.; Nagrial, A. M.; Pajic, M.; Scarlett, C. J.; Pinho, A.; Rooman, I.; Toon, C.; Wu, J.; Pinese, M.; Cowley, M.; Barbour, A.; Mawson, A.; Humphrey, E. S.; Colvin, E. K.; Chou, A.; Lovell, J. A.; Jamieson, N. B.; Duthie, F.; Gingras, M. C.; Fisher, W. E.; Dagg, R. A.; Lau, L. M.; Lee, M.; Pickett, H. A.; Reddel, R. R.; Samra, J. S.; Kench, J. G.; Merrett, N. D.; Epari, K.; Nguyen, N. Q.; Zeps, N.; Falconi, M.; Simbolo, M.; Butturini, G.; Van Buren, G.; Partelli, S.; Fassan, M.; Australian Pancreatic Cancer Genome, Initiative; Khanna, K. K.; Gill, A. J.; Wheeler, D. A.; Gibbs, R. A.; Musgrove, E. A.; Bassi, C.; Tortora, G.; Pederzoli, P., et al.
Responsible Garvan Author Amber Johns
Publisher Name NATURE
Published Date 2017-03-02
Published Volume 543
Published Issue 7643
Published Pages 65-71
Status Published in-print
DOI 10.1038/nature21063
URL link to publisher's version