Substitution mutational signatures in whole-genome–sequenced cancers in the UK population

Andrea Degasperi(University of Cambridge), Xueqing Zou(University of Cambridge), Tauanne Dias Amarante(University of Cambridge), Andrea Martinez-Martinez(University of Cambridge), Ching Chiek Koh(University of Cambridge), João M.L. Dias(University of Cambridge), Laura Heskin(University of Cambridge), Lucia Chmelova(University of Cambridge), Giuseppe Rinaldi(University of Cambridge), Valerie Ya Wen Wang(University of Cambridge), Arjun S. Nanda(University of Cambridge), Aaron Bernstein(University of Cambridge), Sophie Momen(University of Cambridge), Jamie Young(University of Cambridge), D. Perez-Gil(University of Cambridge), Yasin Memari(University of Cambridge), Cherif Badja(University of Cambridge), Scott Shooter(University of Cambridge), Jan Czarnecki(University of Cambridge), Matthew A. Brown(Queen Mary University of London), Helen Davies(University of Cambridge), Serena Nik‐Zainal(University of Cambridge), John C. Ambrose, Paramasivam Arumugam(University of Cambridge), R. Bevers(University of Cambridge), Marta Bleda(Queen Mary University of London), F. Boardman-Pretty(University of Cambridge), C. R. Boustred, Helen Brittain(University of Cambridge), M. J. Caulfield, G. C. Chan(University of Cambridge), Tom Fowler(Queen Mary University of London), Adam Giess, Angela Hamblin, Stephen Henderson(University of Cambridge), Tim Hubbard, R. Jackson(University of Cambridge), J. Louise Jones, Dalia Kasperavičiūtė(University of Cambridge), Melis Kayikci(Queen Mary University of London), Athanasios Kousathanas, L. Lahnstein(University of Cambridge), S. E. A. Leigh(University of Cambridge), Ivone Leong(University of Cambridge), F. J. Lopez, F. Maleady-Crowe(University of Cambridge), Meriel McEntagart(Queen Mary University of London), Federico Minneci(University of Cambridge), Loukas Moutsianas(University of Cambridge), Michael Mueller(Queen Mary University of London), Nirupa Murugaesu(University of Cambridge), Anna C. Need(University of Cambridge), Peter O’Donovan(University of Cambridge), Chris A. Odhams(University of Cambridge), Christine Patch(University of Cambridge), D. Perez-Gil(University of Cambridge), Mariana Buongermino Pereira, J. Pullinger(University of Cambridge), T. Rahim(Queen Mary University of London), Augusto Rendon, T. Rogers(Queen Mary University of London), K. Savage(University of Cambridge), K. Sawant(University of Cambridge), Richard H. Scott(University of Cambridge), Afshan Siddiq, A. Sieghart, Sean Smith(University of Cambridge), Alona Sosinsky, Alexander Stuckey, M. Tanguy(Queen Mary University of London), Ana Lisa Taylor Tavares(University of Cambridge), Elaine Thomas(University of Cambridge), Simon R. Thompson, Arianna Tucci, M. J. Welland, Elena Williams(University of Cambridge), Katarzyna Witkowska(University of Cambridge), Scott Wood
Science
April 21, 2022
10.1126/science.abl9283
Cited by 281Open Access
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Abstract

Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We performed mutational signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. We contrasted our results to two independent cancer WGS datasets, the International Cancer Genome Consortium (ICGC) and Hartwig Foundation, involving 18,640 WGS cancers in total. Our analyses add 40 single and 18 double substitution signatures to the current mutational signature tally. Critically, we show for each organ, that cancers have a limited number of 'common' signatures and a long tail of 'rare' signatures. We provide a practical solution for utilizing this concept of common versus rare signatures in future analyses.

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