TY - JOUR T1 - Large-scale analysis of genome and transcriptome alterations in multiple tumors unveils novel cancer-relevant splicing networks JF - bioRxiv DO - 10.1101/023010 SP - 023010 AU - Endre Sebestyén AU - Babita Singh AU - Belén Miñana AU - Amadís Pagès AU - Francesca Mateo AU - Miguel Angel Pujana AU - Juan Valcárcel AU - Eduardo Eyras Y1 - 2015/01/01 UR - http://biorxiv.org/content/early/2015/08/02/023010.abstract N2 - Alternative splicing is a molecular mechanism regulated by RNA-binding proteins and affecting most eukaryotic genes. However, its role in human diseases, including cancer, is only starting to be unveiled. We systematically analyzed the 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 that are associated with multiple alternative splicing changes in cancer drivers and oncogenic pathways. Remarkably, breast and other tumors recapitulate splicing patterns similar to undifferentiated cells. These patterns, mainly controlled by MBNL1, involve multiple cancer drivers, including the mitotic gene NUMA1. We show that NUMA1 alternative splicing contributes to enhanced cell proliferation and induces centrosome amplification in non-tumorigenic mammary epithelial cells. Our study uncovers novel splicing networks that potentially contribute to cancer development and progression. ER -