Revealing the Determinants of Widespread Alternative Splicing Perturbation in Cancer

Abstract

SUMMARY It is increasingly appreciated that alternative splicing plays a key role in generating functional specificity and diversity in cancer. However, the mechanisms by which cancer mutations perturb splicing remain unknown. Here, we developed a network-based strategy, DrAS-Net, to investigate over 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events. We identified over 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact. Strikingly, tumors with splicing perturbations show reduced expression of immune system-related genes, and increased expression of cell proliferation markers. Tumors harboring different mutations in the same gene often exhibit distinct splicing perturbations. Further stratification of 10,000 patients based on their mutation-splicing relationships identifies subtypes with distinct clinical features, including survival rates. Our work reveals how single nucleotide changes can alter the repertoires of splicing isoforms, providing insights into oncogenic mechanisms for precision medicine.

Integrated Analysis of the Functions and Prognostic Values of RNA Binding Proteins in Lung Squamous Cell Carcinoma

“…The downregulated RBPs were mainly enriched in the mRNA metabolic process, RNA processing, regulation of translation, TGF-beta signaling pathway, and Toll-like receptor signaling pathway. In recent years, a large number of studies, have reported the role of aberrant RNA metabolism and RNA processing in various diseases (Li et al, 2017(Li et al, , 2018Li S. et al, 2019;. RNA processing factors were shown to have increased expression in poorly differentiated non-small-cell lung cancer cells (Geles et al, 2016).…”

Transcriptome‐Wide Analysis Reveals the Landscape of Aberrant Alternative Splicing Events in Liver Cancer

“…Increasing evidence indicates that deleterious mutations (including nonsense, missense, and even translationally silent mutations) residing within splicing regulatory regions exert effects on pre‐mRNA splicing in human diseases . For example, a recent pan‐cancer study revealed how point mutations can alter repertoires of splicing isoforms by connecting thousands of mutation‐splicing relationships across 33 types of cancer . Nevertheless, understanding of the dysregulation of splicing machinery components in HCC remains unclear.…”

MERIT: Systematic Analysis and Characterization of Mutational Effect on RNA Interactome Topology

“…This computational framework has not only validated the experimental results observed in HCC but also provided insights into the RBP–gene regulatory networks across cancer types. In addition, alternative splicing (AS) is a process highly regulated by RBPs . Integration of AS data sets will provide novel insights into our understanding of RBP regulation in cancer.…”