RT Journal Article
SR Electronic
T1 Germline determinants of the somatic mutation landscape in 2,642 cancer genomes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 208330
DO 10.1101/208330
A1 Sebastian M Waszak
A1 Grace Tiao
A1 Bin Zhu
A1 Tobias Rausch
A1 Francesc Muyas
A1 Bernardo Rodríguez-Martín
A1 Raquel Rabionet
A1 Sergei Yakneen
A1 Georgia Escaramis
A1 Yilong Li
A1 Natalie Saini
A1 Steven A Roberts
A1 German M Demidov
A1 Esa Pitkänen
A1 Olivier Delaneau
A1 Jose Maria Heredia-Genestar
A1 Joachim Weischenfeldt
A1 Suyash S Shringarpure
A1 Jieming Chen
A1 Hidewaki Nakagawa
A1 Ludmil B Alexandrov
A1 Oliver Drechsel
A1 L Jonathan Dursi
A1 Ayellet V Segre
A1 Erik Garrison
A1 Serap Erkek
A1 Nina Habermann
A1 Lara Urban
A1 Ekta Khurana
A1 Andy Cafferkey
A1 Shuto Hayashi
A1 Seiya Imoto
A1 Lauri A Aaltonen
A1 Eva G Alvarez
A1 Adrian Baez-Ortega
A1 Matthew Bailey
A1 Mattia Bosio
A1 Alicia L Bruzos
A1 Ivo Buchhalter
A1 Carlos D. Bustamante
A1 Claudia Calabrese
A1 Anthony DiBiase
A1 Mark Gerstein
A1 Aliaksei Z Holik
A1 Xing Hua
A1 Kuan-lin Huang
A1 Ivica Letunic
A1 Leszek J Klimczak
A1 Roelof Koster
A1 Sushant Kumar
A1 Mike McLellan
A1 Jay Mashl
A1 Lisa Mirabello
A1 Steven Newhouse
A1 Aparna Prasad
A1 Gunnar Rätsch
A1 Matthias Schlesner
A1 Roland Schwarz
A1 Pramod Sharma
A1 Tal Shmaya
A1 Nikos Sidiropoulos
A1 Lei Song
A1 Hana Susak
A1 Tomas Tanskanen
A1 Marta Tojo
A1 David C Wedge
A1 Mark Wright
A1 Ying Wu
A1 Kai Ye
A1 Venkata D Yellapantula
A1 Jorge Zamora
A1 Atul J Butte
A1 Gad Getz
A1 Jared Simpson
A1 Li Ding
A1 Tomas Marques-Bonet
A1 Arcadi Navarro
A1 Alvis Brazma
A1 Peter Campbell
A1 Stephen J Chanock
A1 Nilanjan Chatterjee
A1 Oliver Stegle
A1 Reiner Siebert
A1 Stephan Ossowski
A1 Olivier Harismendy
A1 Dmitry A Gordenin
A1 Jose MC Tubio
A1 Francisco M De La Vega
A1 Douglas F Easton
A1 Xavier Estivill
A1 Jan O Korbel
A1 on behalf of the PCAWG Germline Working group %
A1 and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
YR 2017
UL http://biorxiv.org/content/early/2017/11/01/208330.abstract
AB Cancers develop through somatic mutagenesis, however germline genetic variation can markedly contribute to tumorigenesis via diverse mechanisms. We discovered and phased 88 million germline single nucleotide variants, short insertions/deletions, and large structural variants in whole genomes from 2,642 cancer patients, and employed this genomic resource to study genetic determinants of somatic mutagenesis across 39 cancer types. Our analyses implicate damaging germline variants in a variety of cancer predisposition and DNA damage response genes with specific somatic mutation patterns. Mutations in the MBD4 DNA glycosylase gene showed association with elevated C>T mutagenesis at CpG dinucleotides, a ubiquitous mutational process acting across tissues. Analysis of somatic structural variation exposed complex rearrangement patterns, involving cycles of templated insertions and tandem duplications, in BRCA1-deficient tumours. Genome-wide association analysis implicated common genetic variation at the APOBEC3 gene cluster with reduced basal levels of somatic mutagenesis attributable to APOBEC cytidine deaminases across cancer types. We further inferred over a hundred polymorphic L1/LINE elements with somatic retrotransposition activity in cancer. Our study highlights the major impact of rare and common germline variants on mutational landscapes in cancer.