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.

DDX54 regulates transcriptome dynamics during DNA damage response

“…As a potent regulator of the gene expression during the DDR, DDX54 has the potential to be important for tumor biology. To address this, we analyzed The Cancer Genome Atlas (TCGA) mRNA-seq data (Sebestyén et al 2016) from 11 solid tumor types and found that DDX54 expression was elevated in nine of them (Supplemental Fig. S10B), suggesting its potential role as a novel tumor marker.…”

“…Specifically, some RNA processing factors (EWSR1, THRAP3, RBMX, NONO, HRNPC, YBX1, RBM14) can be either recruited to DSBs, relocalized upon DNA damage and/or directly contribute to DNA repair (Paronetto et al 2011;Rajesh et al 2011;Adamson et al 2012;Beli et al 2012;Krietsch et al 2012;Polo et al 2012;Anantha et al 2013;Chang et al 2014;Shkreta and Chabot 2015;Simon et al 2017), whereas others such as SRSF10 impact alternative splicing of transcripts coding for proteins involved in DNA repair, cell cycle control, and apoptosis (Shkreta et al 2016). Notably, somatic mutations very often occur in genes encoding RNA splicing factors, thus leading to widespread misregulated splicing events in many tumor types (Sebestyén et al 2016). DDR also results in rapid nucleolar segregation and/or disruption upon UV or IR exposure (Olson 2004;Boulon et al 2010).…”

Identification of protein features encoded by alternative exons using Exon Ontology

“…Alternative splicing plays a major role in several pathological situations, as massive splicing variation is observed in many diseases (Cieply and Carstens 2015;Daguenet et al 2015;Sebestyen et al 2016). However, the analysis of the cellular functions driven by specific splicing-derived protein isoforms is a major challenge for two main reasons.…”

How do messenger RNA splicing alterations drive myelodysplasia?

“…Results from studies attempting to define alterations in splicing across histologic and genetic subsets of a variety of cancers using publically deposited data have yielded distinct findings likely related to methodological differences. [53][54][55][56] Conclusion: the importance of rigorously defining aberrant splicing events mediated by RNA splicing factors Most of the questions posed above about the role of mutated RNA splicing factors in MDS pathogenesis center around the effects of these proteins on RNA splicing at a global or transcript-specific level. It is important to note that currently only a handful of aberrant splicing events have been rigorously molecularly characterized as being aberrantly spliced by mutant RNA splicing factors.…”