Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes-Reference-Cited by-同舟云学术

Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes

Published:2017-12-23 Issue: Volume: Page:
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Rheinbay Esther^ORCID,Nielsen Morten Muhlig^ORCID,Abascal Federico,Tiao Grace^ORCID,Hornshøj Henrik,Hess Julian M.^ORCID,Pedersen Randi Istrup^ORCID,Feuerbach Lars^ORCID,Sabarinathan Radhakrishnan^ORCID,Madsen Tobias^ORCID,Kim Jaegil^ORCID,Mularoni Loris^ORCID,Shuai Shimin^ORCID,Lanzós Andrés^ORCID,Herrmann Carl^ORCID,Maruvka Yosef E.,Shen Ciyue,Amin Samirkumar B.^ORCID,Bertl Johanna^ORCID,Dhingra Priyanka^ORCID,Diamanti Klev^ORCID,Gonzalez-Perez Abel^ORCID,Guo Qianyun^ORCID,Haradhvala Nicholas J.^ORCID,Isaev Keren,Juul Malene^ORCID,Komorowski Jan^ORCID,Kumar Sushant^ORCID,Lee Donghoon^ORCID,Lochovsky Lucas^ORCID,Liu Eric Minwei^ORCID,Pich Oriol^ORCID,Tamborero David^ORCID,Umer Husen M.^ORCID,Uusküla-Reimand Liis,Wadelius Claes^ORCID,Wadi Lina,Zhang Jing^ORCID,Boroevich Keith A.^ORCID,Carlevaro-Fita Joana^ORCID,Chakravarty Dimple,Chan Calvin W.Y.^ORCID,Fonseca Nuno A.,Hamilton Mark P.,Hong Chen,Kahles Andre^ORCID,Kim Youngwook,Lehmann Kjong-Van^ORCID,Johnson Todd A.^ORCID,Kahraman Abdullah^ORCID,Park Keunchil,Saksena Gordon^ORCID,Sieverling Lina^ORCID,Sinnott-Armstrong Nicholas A.^ORCID,Campbell Peter J.,Hobolth Asger^ORCID,Kellis Manolis^ORCID,Lawrence Michael S.,Raphael Ben^ORCID,Rubin Mark A.^ORCID,Sander Chris,Stein Lincoln^ORCID,Stuart Josh,Tsunoda Tatsuhiko^ORCID,Wheeler David A.^ORCID,Johnson Rory^ORCID,Reimand Jüri,Gerstein Mark B.^ORCID,Khurana Ekta^ORCID,López-Bigas Núria^ORCID,Martincorena Iñigo^ORCID,Pedersen Jakob Skou^ORCID,Getz Gad^ORCID

Abstract

AbstractDiscovery of cancer drivers has traditionally focused on the identification of protein-coding genes. Here we present a comprehensive analysis of putative cancer driver mutations in both protein-coding and non-coding genomic regions across >2,500 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We developed a statistically rigorous strategy for combining significance levels from multiple driver discovery methods and demonstrate that the integrated results overcome limitations of individual methods. We combined this strategy with careful filtering and applied it to protein-coding genes, promoters, untranslated regions (UTRs), distal enhancers and non-coding RNAs. These analyses redefine the landscape of non-coding driver mutations in cancer genomes, confirming a few previously reported elements and raising doubts about others, while identifying novel candidate elements across 27 cancer types. Novel recurrent events were found in the promoters or 5’UTRs ofTP53, RFTN1, RNF34,andMTG2,in the 3’UTRs ofNFKBIZandTOB1,and in the non-coding RNARMRP.We provide evidence that the previously reported non-coding RNAsNEAT1andMALAT1may be subject to a localized mutational process. Perhaps the most striking finding is the relative paucity of point mutations driving cancer in non-coding genes and regulatory elements. Though we have limited power to discover infrequent non-coding drivers in individual cohorts, combined analysis of promoters of known cancer genes show little excess of mutations beyondTERT.

Publisher

Cold Spring Harbor Laboratory

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