Pathogenic impact of isoform switches in 1209 cancer samples covering 27 cancer types using an isoform-specific interaction network

Abstract

Under normal conditions, cells of almost all tissues types express the same predominant canonical transcript isoform at each gene locus. In cancer, however, splicing regulation is often disturbed, leading to cancer-specific switches in the most dominant transcripts (MDT). But what is the pathogenic impact of these switches and how are they driving oncogenesis? To address these questions, we have developed CanIsoNet, a novel isoform-specific protein-protein interaction network that identifies binding domain losses and interaction disruptions in known alternatively spliced isoforms. We applied CanIsoNet on 1209 cancer samples covering 27 different cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project of the International Cancer Genomics Consortium (ICGC). Our study revealed large variations in the number of cancer-specific MDTs (cMDT) between cancer types. While carcinomas of the head and neck, and brain had none or few cMDT switches, cancers of the female reproduction organs showed the highest number of cMDTs. Interestingly, in contrast to the mutational load the cMDT load was tissue-specific, i.e. cancers arising from the same primary tissue had a similar number of cMDTs. Some cMDT switches were found in 100% of all samples in a cancer type, making them candidates for diagnostic biomarkers. cMDTs showed a tendency to fall at densely populated network regions where they disrupted protein interactions in the proximity of pathogenic cancer genes. A gene ontology enrichment analysis showed that these disruptions occurred mostly in enzyme signaling, protein translation, and RNA splicing pathways. Interestingly, no significant correlation between the number of cMDT switches and the number of coding and non-coding mutations was found. However, for some transcripts, we show that their expression correlates with mutations in non-coding splice-site and promoter regions of their genes.