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

Esther Rheinbay, Morten Muhlig Nielsen, Federico Abascal, Grace Tiao, Henrik Hornshøj, Julian M Hess, Randi Istrup Istrup Pedersen, Lars Feuerbach, Radhakrishnan Sabarinathan, Henrik Tobias Madsen, JAEGIL KIM, Loris Mularoni (+61 others)
2017 bioRxiv   pre-print

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https://web.archive.org/web/20190502050406/https://www.biorxiv.org/content/biorxiv/early/2017/12/23/237313.full.pdf

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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
more » ... rcome 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.
doi:10.1101/237313 fatcat:gt5imzwlure6vojs6hd3yxmb7a
Citation

Esther Rheinbay, Morten Muhlig Nielsen, Federico Abascal, Grace Tiao, Henrik Hornshøj, Julian M Hess, Randi Istrup Istrup Pedersen, Lars Feuerbach, Radhakrishnan Sabarinathan, Henrik Tobias Madsen, JAEGIL KIM, Loris Mularoni, Shimin Shuai, Andrés Arturo Lanzós Camaioni, Carl Herrmann, Yosef E Maruvka, Ciyue Shen, Samir B Amin, Johanna Bertl, Priyanka Dhingra, Klev Diamanti, Abel Gonzalez-Perez, Qianyun Guo, Nicholas J Haradhvala, Keren Isaev, Malene Juul, Jan Komorowski, sushant kumar, Donghoon Lee, Lucas Lochovsky, Eric Minwei Minwei Liu, Oriol Pich, david tamborero, Husen M. Umer, Liis Uusküla-Reimand, Claes Wadelius, Lina Wadi, Jing Zhang, Keith A Boroevich, Joana Carlevaro-Fita, Dimple Chakravarty, Calvin Wing Yiu YW Chan, Nuno A Fonseca, Mark P Hamilton, Chen Hong, Andre Kahles, Youngwook Kim, Kjong-Van Lehmann, Todd Andrew A Johnson, Abdullah Kahraman, Keunchil Park, Gordon Saksena, Lina Sieverling, Nicholas A Sinnott-Armstrong, Peter J Campbell, Asger Hobolth, Manolis Kellis, Michael S Lawrence, Ben Raphael, Mark A Rubin, Chris Sander, Lincoln Stein, Josh Stuart, Tatsuhiko Tsunoda, David A Wheeler, Rory Johnson, Jüri Reimand, Mark B Gerstein, Ekta Khurana, Nuria Lopez-Bigas, Inigo Martincorena, Jakob Skou Skou Pedersen, Gad Getz. "Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes." bioRxiv (2017)