title: Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks.
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.
authors.affiliation: Universitat Pompeu Fabra, E08003 Barcelona, Spain;
authors.forename: Endre
authors.initials: E
authors.lastname: Sebestyén
authors.affiliation: Universitat Pompeu Fabra, E08003 Barcelona, Spain;
authors.forename: Babita
authors.initials: B
authors.lastname: Singh
authors.affiliation: Universitat Pompeu Fabra, E08003 Barcelona, Spain; Centre for Genomic Regulation, E08003 Barcelona, Spain;
authors.forename: Belén
authors.initials: B
authors.lastname: Miñana
authors.affiliation: Universitat Pompeu Fabra, E08003 Barcelona, Spain;
authors.forename: Amadís
authors.initials: A
authors.lastname: Pagès
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), E08908 L'Hospitalet del Llobregat, Spain;
authors.forename: Francesca
authors.initials: F
authors.lastname: Mateo
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), E08908 L'Hospitalet del Llobregat, Spain;
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Pujana
authors.affiliation: Universitat Pompeu Fabra, E08003 Barcelona, Spain; Centre for Genomic Regulation, E08003 Barcelona, Spain; Catalan Institution for Research and Advanced Studies, E08010 Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Valcárcel
authors.affiliation: Universitat Pompeu Fabra, E08003 Barcelona, Spain; Catalan Institution for Research and Advanced Studies, E08010 Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Eyras
mesh_terms: D017398:Alternative Splicing; D020816:Amino Acid Motifs; D001665:Binding Sites; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D000072260:RNA Splicing Factors / Q000502:physiology; D059467:Transcriptome
chemical_list: D000072260:RNA Splicing Factors