Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes
Morten Muhlig Nielsen,
Julian M. Hess,
Jakob Skou Pedersen,
Yosef E Maruvka,
Nicholas J. Haradhvala,
Husen M. Umer,
Keith A Boroevich,
Calvin W.Y. Chan,
Nuno A. Fonseca,
Mark P. Hamilton,
Nicholas A. Sinnott-Armstrong,
Peter J. Campbell,
Michael S Lawrence,
Benjamin J. Raphael,
Mark A. Rubin,
David A. Wheeler,
Mark B. Gerstein,
Posted 23 Dec 2017
bioRxiv DOI: 10.1101/237313
Posted 23 Dec 2017
Discovery 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 of TP53, RFTN1, RNF34, and MTG2, in the 3'UTRs of NFKBIZ and TOB1, and in the non-coding RNA RMRP. We provide evidence that the previously reported non-coding RNAs NEAT1 and MALAT1 may 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 beyond TERT.
- Downloaded 5,114 times
- Download rankings, all-time:
- Site-wide: 763 out of 92,758
- In genomics: 153 out of 5,851
- Year to date:
- Site-wide: 5,113 out of 92,758
- Since beginning of last month:
- Site-wide: 12,939 out of 92,758
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!