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bioRxiv · 10.1101/2025.10.16.682783

Aberrant splicing in human cancer has a large-scale functional impact on transcription factors

Newaz, K.·Tsoy, O.·Baumbach, J.
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Abstract

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 comprehensive systematic analysis of how cancer-specific AS could affect functions 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 potential functional perturbations of TFs due to AS across 15 cancer types. By analyzing AS patterns, we identified 2 118 perturbed AS events (i.e., events showing significant AS pattern differences between normal and paired cancer samples) that affect 718 TFs across 14 cancer types. In 189 TFs, the perturbed AS events affected known functional domains of TFs. Indirect evidence for the functional impact of cancer-specific AS on TFs were also found: First, by relating AS patterns of the perturbed AS events with the DNA-binding and regulatory activity of TFs. Second, by using cancer dependency data to explore whether the affected TFs are essential for cancer cell line proliferation. Our findings show a large-scale functional perturbation of TFs due to cancer-specific AS.

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Newaz, K., Tsoy, O., Baumbach, J.. 2025-10-16. Aberrant splicing in human cancer has a large-scale functional impact on transcription factors. https://doi.org/10.1101/2025.10.16.682783

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