Prognostic importance of splicing-triggered aberrations of protein complex interfaces in cancer

Aberrant alternative splicing (AS) is a prominent hallmark of cancer. AS can perturb protein-protein interactions (PPIs) by adding or removing interface regions of protein complexes encoded by individual exons. Identifying prognostic exon-exon interactions (EEIs) from PPI interfaces can help discover AS-affected cancer-driving PPIs that can serve as potential drug targets. Here, we assessed the prognostic significance of EEIs across 15 cancer types by integrating RNA-seq data with three-dimensional structures of protein complexes. By analyzing the resulting EEI network we identified patient-specific perturbed EEIs (i.e., EEIs present in healthy samples but absent from the paired cancer samples or vice versa ) that were significantly associated with survival. We provide the first evidence that EEIs can be used as prognostic biomarkers for cancer patient survival. Our findings provide mechanistic insights into AS-affected protein-protein interaction interfaces. Given the ongoing expansion of available RNA-seq data and the number of structurally-resolved (or confidently predicted) protein complexes, our computational framework will help accelerate the discovery of clinically important cancer-promoting AS events. ### Competing Interest Statement The authors have declared no competing interest.