Abstract
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.
Highlights
IntroductionCells of almost all tissue types express the same predominant canonical transcript isoform at each gene locus
Under normal conditions, cells of almost all tissue types express the same predominant canonical transcript isoform at each gene locus
Cancer types originating from the same primary tissue, e.g. CNS-GBM and CNS-Oligo, Lung-AdenoCA and Lung-SCC or Lymph-BNHL and Lymph-CLL, tended to have a similar cancer-specific MDT (cMDT) load
Summary
Cells of almost all tissue types express the same predominant canonical transcript isoform at each gene locus. Melanoma tumors often develop drug resistance to BRAF (V600E) inhibitors by expressing a shorter isoform of mutated BRAF that lacks the RAS binding domain and allows BRAF (V600E) proteins to dimerize and signal in a RAS independent m anner[11,12] These phenotypes can arise through alterations in interaction n etworks[13] in which alternative splicing changes the interaction capabilities of gene products by disrupting protein binding domains or protein availability[14]. The Eyras lab discovered in a recent study in over 4,500 cancer samples from 11 cancer types from The Cancer Genome Atlas (TCGA)[18], significant alterations in alternative splicing and MDT switches[19] In their analysis, they were able to show an association between recurrent functional switches in MDT and the loss of protein functions while those gaining functional capabilities were mostly found in oncogenes. Only 4% of these mutations increased splicing efficiency, while the large majority had negative effects on splicing
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