Pathogenic impact of transcript isoform switching in 1,209 cancer samples covering 27 cancer types using an...

Under normal conditions, cells of almost all tissue 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). To address the pathogenic impact of these switches, we have analyzed isoform-specific protein-protein interaction disruptions in 1,209 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 MDT (cMDT) with the highest frequency in cancers of female reproductive organs. Interestingly, in contrast to the mutational load, cancers arising from the same primary tissue had a similar number of cMDT. Some cMDT were found in 100% of all samples in a cancer type, making them candidates for diagnostic biomarkers. cMDT tend to be located 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 protein translation and RNA splicing pathways. Interestingly, samples with mutations in the spliceosomal complex tend to have higher number of cMDT, while other transcript expressions correlated with mutations in non-coding splice-site and promoter regions of their genes. This work demonstrates for the first time the large extent of cancer-specific alterations in alternative splicing for 27 different cancer types. It highlights distinct and common patterns of cMDT and suggests novel pathogenic transcripts and markers that induce large network disruptions in cancers.