RT Journal Article
SR Electronic
T1 Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 237313
DO 10.1101/237313
A1 Rheinbay, Esther
A1 Nielsen, Morten Muhlig
A1 Abascal, Federico
A1 Tiao, Grace
A1 Hornshøj, Henrik
A1 Hess, Julian M.
A1 Pedersen, Randi Istrup
A1 Feuerbach, Lars
A1 Sabarinathan, Radhakrishnan
A1 Madsen, Tobias
A1 Kim, Jaegil
A1 Mularoni, Loris
A1 Shuai, Shimin
A1 Lanzós, Andrés
A1 Herrmann, Carl
A1 Maruvka, Yosef E.
A1 Shen, Ciyue
A1 Amin, Samirkumar B.
A1 Bertl, Johanna
A1 Dhingra, Priyanka
A1 Diamanti, Klev
A1 Gonzalez-Perez, Abel
A1 Guo, Qianyun
A1 Haradhvala, Nicholas J.
A1 Isaev, Keren
A1 Juul, Malene
A1 Komorowski, Jan
A1 Kumar, Sushant
A1 Lee, Donghoon
A1 Lochovsky, Lucas
A1 Liu, Eric Minwei
A1 Pich, Oriol
A1 Tamborero, David
A1 Umer, Husen M.
A1 Uusküla-Reimand, Liis
A1 Wadelius, Claes
A1 Wadi, Lina
A1 Zhang, Jing
A1 Boroevich, Keith A.
A1 Carlevaro-Fita, Joana
A1 Chakravarty, Dimple
A1 Chan, Calvin W.Y.
A1 Fonseca, Nuno A.
A1 Hamilton, Mark P.
A1 Hong, Chen
A1 Kahles, Andre
A1 Kim, Youngwook
A1 Lehmann, Kjong-Van
A1 Johnson, Todd A.
A1 Kahraman, Abdullah
A1 Park, Keunchil
A1 Saksena, Gordon
A1 Sieverling, Lina
A1 Sinnott-Armstrong, Nicholas A.
A1 Campbell, Peter J.
A1 Hobolth, Asger
A1 Kellis, Manolis
A1 Lawrence, Michael S.
A1 Raphael, Ben
A1 Rubin, Mark A.
A1 Sander, Chris
A1 Stein, Lincoln
A1 Stuart, Josh
A1 Tsunoda, Tatsuhiko
A1 Wheeler, David A.
A1 Johnson, Rory
A1 Reimand, Jüri
A1 Gerstein, Mark B.
A1 Khurana, Ekta
A1 López-Bigas, Núria
A1 Martincorena, Iñigo
A1 Pedersen, Jakob Skou
A1 Getz, Gad
YR 2017
UL http://biorxiv.org/content/early/2017/12/23/237313.abstract
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.