Whole-genome landscape of pancreatic neuroendocrine tumours

Scarpa, A. et al. (2017) Whole-genome landscape of pancreatic neuroendocrine tumours. Nature, 543(7643), pp. 65-71. (doi: 10.1038/nature21063) (PMID:28199314)

137698.pdf - Accepted Version



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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Jamieson, Dr Nigel and Biankin, Professor Andrew and Jones, Mr Marc and Nourse, Dr Craig and Bailey, Dr Peter and Musgrove, Dr Elizabeth and Duthie, Dr Fraser and Grimmond, Professor Sean and Chang, Professor David
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.J., Bruxner, T. J.C., 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., Davì, M. V., Landoni, L., Malpaga, A., Miotto, M., Whitehall, V. L.J., 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.S., 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., Khanna, K. K., Gill, A. J., Wheeler, D. A., Gibbs, R. A., Musgrove, E. A., Bassi, C., Tortora, G., Pederzoli, P., Pearson, J. V., Waddell, N., Biankin, A. V., and Grimmond, S.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Nature
Publisher:Nature Publishing Group
ISSN (Online):1476-4687
Published Online:15 February 2017
Copyright Holders:Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature
First Published:First published in Nature 543(7643):65-71
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656911Defining Platinum and PARP Responsive Molecular Phenotypes of Pancreatic Cancer.Andrew BiankinWellcome Trust (WELLCOME)103721/Z/14/ZICS - TRANSLATIONAL RESEARCH CENTRE
645511Genotype Guided Stratified Therapy for Pancreatic CancerAndrew BiankinCancer Research UK (CAN-RES-UK)17263ICS - TRANSLATIONAL RESEARCH CENTRE
645512Genotype Guided Stratified Therapy for Pancreatic CancerAndrew BiankinCancer Research UK (CAN-RES-UK)C29717/A18484ICS - TRANSLATIONAL RESEARCH CENTRE
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CAN-RES-UK)18076RI CANCER SCIENCES
712701Clinical Training Award Cycle 2Andrew BiankinCancer Research UK (CAN-RES-UK)20921ICS - TRANSLATIONAL RESEARCH CENTRE
690421Glasgow Molecular Pathology (GMP) NodeKarin OienMedical Research Council (MRC)MR/N005813/1ICS - EXPERIMENTAL THERAPEUTICS