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

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.

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

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