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

PCAWG Driver Group, PCAWG Driver Group; Lanzos, Andrés (2019). Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes (bioRxiv). Cold Spring Harbor Laboratory 10.1101/237313

[img]
Preview
Text
237313.full.pdf - Published Version
Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND).

Download (8MB) | Preview

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.

Item Type:

Working Paper

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Lanzos Camaioni, Andrés Arturo

Subjects:

600 Technology > 610 Medicine & health

Series:

bioRxiv

Publisher:

Cold Spring Harbor Laboratory

Language:

English

Submitter:

Andrés Arturo Lanzos Camaioni

Date Deposited:

03 Oct 2019 14:37

Last Modified:

05 Dec 2022 15:31

Publisher DOI:

10.1101/237313

Additional Information:

Kollaboration. Es ist nur der Berner Autor namentlich erwähnt. - bioRxiv (pronounced "bio-archive") is a free online archive and distribution service for unpublished preprints in the life sciences.

BORIS DOI:

10.7892/boris.133639

URI:

https://boris.unibe.ch/id/eprint/133639

Actions (login required)

Edit item Edit item
Provide Feedback