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Nature DOI:10.1038/s41586-020-1965-x

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

Publication TypeJournal Article
Year of Publication2020
AuthorsRheinbay, E, Nielsen, MMuhlig, Abascal, F, Wala, JA, Shapira, O, Tiao, G, Hornshøj, H, Hess, JM, Juul, RIstrup, Lin, Z, Feuerbach, L, Sabarinathan, R, Madsen, T, Kim, J, Mularoni, L, Shuai, S, Lanzós, A, Herrmann, C, Maruvka, YE, Shen, C, Amin, SB, Bandopadhayay, P, Bertl, J, Boroevich, KA, Busanovich, J, Carlevaro-Fita, J, Chakravarty, D, Chan, CWing Yiu, Craft, D, Dhingra, P, Diamanti, K, Fonseca, NA, Gonzalez-Perez, A, Guo, Q, Hamilton, MP, Haradhvala, NJ, Hong, C, Isaev, K, Johnson, TA, Juul, M, Kahles, A, Kahraman, A, Kim, Y, Komorowski, J, Kumar, K, Kumar, S, Lee, D, Van Lehmann, K-, Li, Y, Liu, EMinwei, Lochovsky, L, Park, K, Pich, O, Roberts, ND, Saksena, G, Schumacher, SE, Sidiropoulos, N, Sieverling, L, Sinnott-Armstrong, N, Stewart, C, Tamborero, D, Tubio, JMC, Umer, HM, Uusküla-Reimand, L, Wadelius, C, Wadi, L, Yao, X, Zhang, C-Z, Zhang, J, Haber, JE, Hobolth, A, Imielinski, M, Kellis, M, Lawrence, MS, von Mering, C, Nakagawa, H, Raphael, BJ, Rubin, MA, Sander, C, Stein, LD, Stuart, JM, Tsunoda, T, Wheeler, DA, Johnson, R, Reimand, J, Gerstein, M, Khurana, E, Campbell, PJ, López-Bigas, N, Weischenfeldt, J, Beroukhim, R, Martincorena, I, Pedersen, JSkou, Getz, G
Corporate AuthorsPCAWG Drivers and Functional Interpretation Working Group, PCAWG Structural Variation Working Group, PCAWG Consortium
JournalNature
Volume578
Issue7793
Pages102-111
Date Published2020 02
ISSN1476-4687
Abstract

The discovery of drivers of cancer has traditionally focused on protein-coding genes. 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 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, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 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.

DOI10.1038/s41586-020-1965-x
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/32025015?dopt=Abstract

Alternate JournalNature
PubMed ID32025015
PubMed Central IDPMC7054214
Grant ListR01 CA188228 / CA / NCI NIH HHS / United States
U54 CA143798 / CA / NCI NIH HHS / United States
R01 HG007069 / HG / NHGRI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
R01 CA215489 / CA / NCI NIH HHS / United States
U24 CA210999 / CA / NCI NIH HHS / United States
R35 GM127029 / GM / NIGMS NIH HHS / United States
U24 CA211000 / CA / NCI NIH HHS / United States