Analyses of non-coding somatic drivers in 2,658 cancer whole genomes
Author(s)
Rheinbay, Esther; Nielsen, Morten Muhlig; Abascal, Federico; Wala, Jeremiah A.; Shapira, Ofer; Tiao, Grace; Hornshøj, Henrik; Hess, Julian M.; Juul, Randi Istrup; Lin, Ziao; Feuerbach, Lars; Sabarinathan, Radhakrishnan; Madsen, Tobias; Kim, Jaegil; Mularoni, Loris; Shuai, Shimin; Lanzós, Andrés; Herrmann, Carl; Maruvka, Yosef E.; Shen, Ciyue; Amin, Samirkumar B.; Bandopadhayay, Pratiti; Bertl, Johanna; Boroevich, Keith A.; Busanovich, John; Carlevaro-Fita, Joana; Chakravarty, Dimple; Chan, Calvin Wing Yiu; Craft, David; Dhingra, Priyanka; Diamanti, Klev; Fonseca, Nuno A.; Gonzalez-Perez, Abel; Guo, Qianyun; Hamilton, Mark P.; Haradhvala, Nicholas J.; Hong, Chen; Isaev, Keren; Johnson, Todd A.; Juul, Malene; Kahles, Andre; Kahraman, Abdullah; Kim, Youngwook; Komorowski, Jan; Kumar, Kiran; Kumar, Sushant; Lee, Donghoon; Lehmann, Kjong-Van; Li, Yilong; Liu, Eric Minwei; Lochovsky, Lucas; Park, Keunchil; Pich, Oriol; Roberts, Nicola D.; Saksena, Gordon; Schumacher, Steven E.; Sidiropoulos, Nikos; Sieverling, Lina; Sinnott-Armstrong, Nasa; Stewart, Chip; Tamborero, David; Tubio, Jose M. C.; Umer, Husen M.; Uusküla-Reimand, Liis; Wadelius, Claes; Wadi, Lina; Yao, Xiaotong; Zhang, Cheng-Zhong; Zhang, Jing; Haber, James E.; Hobolth, Asger; Imielinski, Marcin; Kellis, Manolis; Lawrence, Michael S.; von Mering, Christian; Nakagawa, Hidewaki; Raphael, Benjamin J.; Rubin, Mark A.; Sander, Chris; Stein, Lincoln D.; Stuart, Joshua M.; Tsunoda, Tatsuhiko; Wheeler, David A.; Johnson, Rory; Reimand, Jüri; Gerstein, Mark; Khurana, Ekta; Campbell, Peter J.; López-Bigas, Núria; Weischenfeldt, Joachim; Beroukhim, Rameen; Martincorena, Iñigo; Pedersen, Jakob Skou; Getz, Gad; ... Show more Show less
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<jats:title>Abstract</jats:title><jats:p>The discovery of drivers of cancer has traditionally focused on protein-coding genes<jats:sup>1–4</jats:sup>. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium<jats:sup>5</jats:sup> of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers<jats:sup>6,7</jats:sup>, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of <jats:italic>TP53</jats:italic>, in the 3′ untranslated regions of <jats:italic>NFKBIZ</jats:italic> and <jats:italic>TOB1</jats:italic>, focal deletions in <jats:italic>BRD4</jats:italic> and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.</jats:p>
Date issued
2020-02Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence LaboratoryJournal
Nature
Publisher
Springer Science and Business Media LLC
ISSN
0028-0836
1476-4687