Whole-genome landscape of pancreatic neuroendocrine tumours.

Authors:
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

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, 3010, Victoria, Australia.

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.

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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017
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