Probing Isoform Switching Events in Various Cancer Types: Lessons From Pan-Cancer Studies

Abstract

Alternative splicing is an essential regulatory mechanism for gene expression in mammalian cells contributing to protein, cellular, and species diversity. In cancer, alternative splicing is frequently disturbed, leading to changes in the expression of alternatively spliced protein isoforms. Advances in sequencing technologies and analysis methods led to new insights into the extent and functional impact of disturbed alternative splicing events. In this review, we give a brief overview of the molecular mechanisms driving alternative splicing, highlight the function of alternative splicing in healthy tissues and describe how alternative splicing is disrupted in cancer. We summarize current available computational tools for analyzing differential transcript usage, isoform switching events, and the pathogenic impact of cancer-specific splicing events. Finally, the strategies of three recent pan-cancer studies on isoform switching events are compared. Their methodological similarities and discrepancies are highlighted and lessons learned from the comparison are listed. We hope that our assessment will lead to new and more robust methods for cancer-specific transcript detection and help to produce more accurate functional impact predictions of isoform switching events.

Quantitative Analysis of Isoform Switching in Cancer

“…Remarkably, overlap between the original results of Sebetyen et al and the results obtained after applying their pipeline to our dataset was also quite low; only 40 unique genes were shared between them (approximately 17% of each result in terms of unique genes). Therefore, we cautiously argue that the choice of annotation and RNA-Seq analysis strategy might in fact account for a significant portion of discrepancy between studies investigating isoform switching, something that has been suggested before [ 23 ]. However, due to the large differences between studies in terms of methodology and technical aspects, proving this statement for certain is a tough task outside of the scope of the present work.…”

Alternative Splicing in Pancreatic Ductal Adenocarcinoma Leads to Dysregulated Immune System

“…№ 1. doi: 10.17537/2024. 19.15 30% higher rate than in normal cells [55]. Isoform switching leads to the loss of DNA sequences encoding protein domains, significant changes in amino acid sequences, alteration of protein domains, and modification of signal peptides.…”

“…Isoform switching (AS) is a complex and highly regulated process that contributes to proteome diversity. In normal cells, isoforms play a crucial role in regulating various biological processes; however, their abnormal expression contributes to tumorigenesis [55]. There are five major types of alternative splicing events regarding splice site selection, including (exon skipping, mutually exclusive exons, intron retention, alternative 5 splice site, and alternative 3 splice site) [56].…”