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Germline determinants of the somatic mutation landscape in 2,642 cancer genomes

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Item Type:Preprint
Title:Germline determinants of the somatic mutation landscape in 2,642 cancer genomes
Creators Name:Waszak, S.M. and Tiao, G. and Zhu, B. and Rausch, T. and Muyas, F. and Rodriguez-Martin, B. and Rabionet, R. and Yakneen, S. and Escaramis, G. and Li, Y. and Saini, N. and Roberts, S.A. and Demidov, G.M. and Pitkanen, E. and Delaneau, O. and Heredia-Genestar, J.M. and Weischenfeldt, J. and Shringarpure, S.S. and Chen, J. and Nakagawa, H. and Alexandrov, L.B. and Drechsel, O. and Dursi, L.J. and Segre, A.V. and Garrison, E. and Erkek, S. and Habermann, N. and Urban, L. and Khurana, E. and Cafferkey, A. and Hayashi, S. and Imoto, S. and Aaltonen, L.A. and Alvarez, E.G. and Baez-Ortega, A. and Bailey, M. and Bosio, M. and Bruzos, A.L. and Buchhalter, I. and Bustamante, C.D. and Calabrese, C. and DiBiase, A. and Gerstein, M. and Holik, A.Z. and Hua, X. and Huang, K.l. and Letunic, I. and Klimczak, L.J. and Koster, R. and Kumar, S. and McLellan, M. and Mashl, J. and Mirabello, L. and Newhouse, S. and Prasad, A. and Raetsch, G. and Schlesner, M. and Schwarz, R. and Sharma, P. and Shmaya, T. and Sidiropoulos, N. and Song, L. and Susak, H. and Tanskanen, T. and Tojo, M. and Wedge, D.C. and Wright, M. and Wu, Y. and Ye, K. and Yellapantula, V. D. and Zamora, J. and Butte, A.J. and Getz, G. and Simpson, J. and Ding, L. and Marques-Bonet, T. and Navarro, A. and Brazma, A. and Campbell, P. and Chanock, S.J. and Chatterjee, N. and Stegle, O. and Siebert, R. and Ossowski, S. and Harismendy, O. and Gordenin, D.A. and Tubio, J.M.C. and De La Vega, F.M. and Easton, D.F. and Estivill, X. and Korbel, J.
Abstract: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.
Source:bioRxiv
Publisher:Cold Spring Harbor Laboratory (U.S.A.)
Article Number:208330
Date:1 November 2017
Official Publication:https://doi.org/10.1101/208330

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