Jul 22, 2015

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

BioRxiv : the Preprint Server for Biology
Endre SebestyénEduardo Eyras

Abstract

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.

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Mentioned in this Paper

MBNL1 gene
Study
Biochemical Pathway
Patterns
Genome
Genes
Mammary Gland
NUMA1
Squamous Transitional Epithelial Cell Count
Trans-Spliced Leader Sequences

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