Aberrant splicing in human cancer shows possible functional impact on transcription factors

Cancer shows aberrant alternative splicing (AS), which could functionally perturb proteins required for normal cellular behavior. Transcription factors (TFs) are proteins that regulate gene transcription. Some evidence about AS-driven perturbation of TFs in cancer has been documented. A systematic analysis of how cancer-specific AS could affect structural or functional characteristics of TFs is missing. Such an analysis could reveal the molecular mechanisms of cancer progression due to transcription misregulations, and thus could help identify therapeutic targets. Here, we systematically analyzed AS-induced structural and potential functional perturbations of TFs across 15 cancer types. We identified 2170 perturbed AS events (i.e., events showing significant AS pattern differences between normal and paired cancer samples) that affect 727 TFs across 14 cancer types. In 205 TFs, the perturbed AS events affect known functional domains of TFs. Additional evidence for a potential functional impact of cancer-specific AS on TFs was also found by (1) relating AS patterns of the perturbed AS events with the DNA-binding and regulatory activity of TFs and (2) using cancer dependency data to explore whether the affected TFs are essential for cancer cell line proliferation. Our findings show a large-scale, likely functional, perturbation of TFs due to cancer-specific AS.