PT  - JOURNAL ARTICLE
AU  - Rheinbay, Esther
AU  - Nielsen, Morten Muhlig
AU  - Abascal, Federico
AU  - Tiao, Grace
AU  - Hornshøj, Henrik
AU  - Hess, Julian M.
AU  - Pedersen, Randi Istrup
AU  - Feuerbach, Lars
AU  - Sabarinathan, Radhakrishnan
AU  - Madsen, Tobias
AU  - Kim, Jaegil
AU  - Mularoni, Loris
AU  - Shuai, Shimin
AU  - Lanzós, Andrés
AU  - Herrmann, Carl
AU  - Maruvka, Yosef E.
AU  - Shen, Ciyue
AU  - Amin, Samirkumar B.
AU  - Bertl, Johanna
AU  - Dhingra, Priyanka
AU  - Diamanti, Klev
AU  - Gonzalez-Perez, Abel
AU  - Guo, Qianyun
AU  - Haradhvala, Nicholas J.
AU  - Isaev, Keren
AU  - Juul, Malene
AU  - Komorowski, Jan
AU  - Kumar, Sushant
AU  - Lee, Donghoon
AU  - Lochovsky, Lucas
AU  - Liu, Eric Minwei
AU  - Pich, Oriol
AU  - Tamborero, David
AU  - Umer, Husen M.
AU  - Uusküla-Reimand, Liis
AU  - Wadelius, Claes
AU  - Wadi, Lina
AU  - Zhang, Jing
AU  - Boroevich, Keith A.
AU  - Carlevaro-Fita, Joana
AU  - Chakravarty, Dimple
AU  - Chan, Calvin W.Y.
AU  - Fonseca, Nuno A.
AU  - Hamilton, Mark P.
AU  - Hong, Chen
AU  - Kahles, Andre
AU  - Kim, Youngwook
AU  - Lehmann, Kjong-Van
AU  - Johnson, Todd A.
AU  - Kahraman, Abdullah
AU  - Park, Keunchil
AU  - Saksena, Gordon
AU  - Sieverling, Lina
AU  - Sinnott-Armstrong, Nicholas A.
AU  - Campbell, Peter J.
AU  - Hobolth, Asger
AU  - Kellis, Manolis
AU  - Lawrence, Michael S.
AU  - Raphael, Ben
AU  - Rubin, Mark A.
AU  - Sander, Chris
AU  - Stein, Lincoln
AU  - Stuart, Josh
AU  - Tsunoda, Tatsuhiko
AU  - Wheeler, David A.
AU  - Johnson, Rory
AU  - Reimand, Jüri
AU  - Gerstein, Mark B.
AU  - Khurana, Ekta
AU  - López-Bigas, Núria
AU  - Martincorena, Iñigo
AU  - Pedersen, Jakob Skou
AU  - Getz, Gad
ED  - , 
TI  - Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes
AID  - 10.1101/237313
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 237313
4099  - http://biorxiv.org/content/early/2017/12/23/237313.short
4100  - http://biorxiv.org/content/early/2017/12/23/237313.full
AB  - 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.