Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks

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  • dc.contributor.author Sebestyén, Endreca
  • dc.contributor.author Singh, Babita, 1986-ca
  • dc.contributor.author Miñana Gómez, Belénca
  • dc.contributor.author Pagès Pinós, Amadísca
  • dc.contributor.author Mateo, Francescca
  • dc.contributor.author Pujana, Miguel Angelca
  • dc.contributor.author Valcárcel, J. (Juan)ca
  • dc.contributor.author Eyras Jiménez, Eduardoca
  • dc.date.accessioned 2017-03-31T11:07:16Z
  • dc.date.available 2017-03-31T11:07:16Z
  • dc.date.issued 2016
  • dc.description.abstract Alternative splicing is regulated by multiple RNA-binding proteins and influences the expression of most eukaryotic genes. However, the role of this process in human disease, and particularly in cancer, is only starting to be unveiled. We systematically analyzed mutation, copy number, and gene expression patterns of 1348 RNA-binding protein (RBP) genes in 11 solid tumor types, together with alternative splicing changes in these tumors and the enrichment of binding motifs in the alternatively spliced sequences. Our comprehensive study reveals widespread alterations in the expression of RBP genes, as well as novel mutations and copy number variations in association with multiple alternative splicing changes in cancer drivers and oncogenic pathways. Remarkably, the altered splicing patterns in several tumor types recapitulate those of undifferentiated cells. These patterns are predicted to be mainly controlled by MBNL1 and involve multiple cancer drivers, including the mitotic gene NUMA1. We show that NUMA1 alternative splicing induces enhanced cell proliferation and centrosome amplification in nontumorigenic mammary epithelial cells. Our study uncovers novel splicing networks that potentially contribute to cancer development and progression.
  • dc.description.sponsorship We thank P. Papasaikas, B. Blencowe, M. Irimia, and Q. Morris for comments and discussions. E.S., B.S., A.P., and E.E. were supported by the Ministerio de Economía y Competitividad (MINECO) and European Commission (FEDER) (BIO2014-52566-R), Consolider RNAREG (CSD2009-00080), by Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (SGR2014-1121), and by the Sandra Ibarra Foundation for Cancer (FSI2013). J.V. and B.M. were supported by Fundación Botín, by Banco de Santander through its Santander Universities Global Division, and by Consolider RNAREG (CSD2009-00080), MINECO, and AGAUR. F.M. and M.A.P. were supported by AECC (Hereditary Cancer), AGAUR (SGR2014-364), the Instituto de Salud Carlos III (ISCIII), the MINECO, and FEDER (PIE13/00022-ONCOPROFILE, PI15/00854, and RTICC RD12/0036/0008).
  • dc.format.mimetype application/pdfca
  • dc.identifier.citation Sebestyén E, Singh B, Miñana Gómez B, Pagès Pinós A, Mateo F, Pujana MA et al. Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks. Genome Res. 2016;26(6):732-44. DOI: 10.1101/gr.199935.115
  • dc.identifier.doi http://dx.doi.org/10.1101/gr.199935.115
  • dc.identifier.issn 1088-9051
  • dc.identifier.uri http://hdl.handle.net/10230/28364
  • dc.language.iso eng
  • dc.publisher Cold Spring Harbor Laboratory Press (CSHL Press)ca
  • dc.relation.ispartof Genome Research. 2016;26(6):732-44
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/CSD2009-00080
  • dc.rights © 2016 Sebestyén et al.; Published by Cold Spring Harbor Laboratory Press. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
  • dc.title Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networksca
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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