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.
