Pathway and network analysis of more than 2500 whole cancer genomes

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• dc.contributor.author Reyna, Matthew A.
• dc.contributor.author Haan, David
• dc.contributor.author Paczkowska, Marta
• dc.contributor.author Verbeke, Lieven P.C.
• dc.contributor.author Vazquez, Miguel
• dc.contributor.author Kahraman, Abdullah
• dc.contributor.author Pulido-Tamayo, Sergio
• dc.contributor.author Barenboim, Jonathan
• dc.contributor.author Wadi, Lina
• dc.contributor.author Dhingra, Priyanka
• dc.contributor.author Shrestha, Raunak
• dc.contributor.author Getz, Gad
• dc.contributor.author Lawrence, Michael S.
• dc.contributor.author Pedersen, Jackob S.
• dc.contributor.author Rubin, Mark A.
• dc.contributor.author Wheeler, David A.
• dc.contributor.author Brunak, Søren
• dc.contributor.author Izarzugaza, Jose M.G.
• dc.contributor.author PCAWG Drivers and Functional Interpretation Working Group
• dc.contributor.author PCAWG Consortium
• dc.contributor.author Deu-Pons, Jordi
• dc.contributor.author Gut, Ivo Glynne
• dc.contributor.author Muiños, Ferran
• dc.contributor.author Mularoni, Loris
• dc.contributor.author Rubio Pérez, Carlota, 1990-
• dc.contributor.author Tamborero Noguera, David
• dc.date.accessioned 2020-04-24T07:19:11Z
• dc.date.available 2020-04-24T07:19:11Z
• dc.date.issued 2020
• dc.description.abstract The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.
• dc.description.sponsorship B.J.R. received funding from NIH grants U24CA211000 and R01HG007069. J.M.S. received funding from NIH grants U24CA143858, R01CA180778, and U24CA210990. J.R. received funding from the Ontario Institute for Cancer Research (OICR) Investigator Award provided by the Government of Ontario, Operating Grant from Cancer Research Society (CRS) (#21089), the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant (#RGPIN-2016-06485), and the Canadian Institutes of Health Research (CIHR) Project Grant. K.M. received funding from IWT/SBO NEMOA and FWO 3G046318 and G.0371.06 grants. J.M.G.I. received funding from the Novo Nordisk Foundation (NNF17OC0027594 and NNF14CC0001) and the Innovation Fund Denmark (5184-00102B). S.B. received funding from the Novo Nordisk Foundation (NNF17OC0027594 and NNF14CC0001). J.B. received funding from the BioTalent Canada Student Internship Program. A.V. and M.V. received funding from the Joint BSC-IRB-CRG Program in Computational Biology and the Severo Ochoa Award (SEV 2015-0493). M.A.R. was supported in part by the National Cancer Institute of the NIH (Cancer Target Discovery and Development Network grant U01CA217875)
• dc.format.mimetype application/pdf
• dc.identifier.citation Reyna MA, Haan D, Paczkowska M, Verbeke LPC, Vazquez M, Kahraman A et al. Pathway and network analysis of more than 2500 whole cancer genomes. Nat Commun. 2020 Feb 5; 11(1): 729. DOI: 10.1038/s41467-020-14367-0
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-020-14367-0
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/44323
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nature Communications. 2020 Feb 5;11(1):729
• dc.rights © 2020 Matthew A. Reyna. Open Access 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 Càncer
• dc.subject.other Genòmica
• dc.subject.other Genètica
• dc.title Pathway and network analysis of more than 2500 whole cancer genomes
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion