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

Rheinbay, Esther; Sabarinathan, Radhakrishnan; Mularoni, Loris; Gonzalez-Perez, Abel; Pich, Oriol; Tamborero Noguera, David; López Bigas, Núria; Getz, Gad; PCAWG Consortium

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

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dc.contributor.author Rheinbay, Esther
dc.contributor.author Sabarinathan, Radhakrishnan
dc.contributor.author Mularoni, Loris
dc.contributor.author Gonzalez-Perez, Abel
dc.contributor.author Pich, Oriol
dc.contributor.author Tamborero Noguera, David
dc.contributor.author López Bigas, Núria
dc.contributor.author Getz, Gad
dc.contributor.author PCAWG Consortium
dc.date.accessioned 2020-04-17T07:01:08Z
dc.date.available 2020-04-17T07:01:08Z
dc.date.issued 2020
dc.description.abstract The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. 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) Consortium5 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 drivers6,7, 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.
dc.description.sponsorship Work in the Getz laboratory was partially funded by the GDAC grants (NIH U24CA143845 and NIH U24CA210999), G.G.’s funds at the Broad Institute and MGH. J.S.P. was partially funded by Independent Research Fund Denmark (12-126439 and 7016-00379) and The Danish Cancer Society (R124-A7869). R.B. received funds from the National Institutes of Health (U54CA143798, R01CA188228, R35GM127029, and R01CA215489). J.W. was partly funded by Independent Research Fund Denmark (4183-00233B and 8020-00282B) and Danish Cancer Society (R147-Rp12977). N.L.-B. acknowledges funding from the European Research Council consolidator grant 682398) and Spanish Ministry of Economy and Competitiveness (SAF2015-66084-R, MINECO/FEDER, UE)
dc.format.mimetype application/pdf
dc.identifier.citation Rheinbay E, Nielsen MM, Abascal F, Wala JA, Shapira O, Tiao G et al. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Nature. 2020 Feb; 578(7793): 102-111. DOI: 10.1038/s41586-020-1965-x
dc.identifier.doi http://dx.doi.org/10.1038/s41586-020-1965-x
dc.identifier.issn 0028-0836
dc.identifier.uri http://hdl.handle.net/10230/44262
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Nature. 2020 Feb; 578(7793): 102-11
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/682398
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-66084-R
dc.rights © 2020 Esther Rheinbay et al. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.other Genoma humà
dc.subject.other Tumors -- Genètica
dc.subject.other Mutació (Biologia)
dc.title Analyses of non-coding somatic drivers in 2,658 cancer whole genomes
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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