Switches in alternatively spliced isoforms impact protein and drug interactions in melanoma, ovarian cancer, and acute myeloid leukemia

Background Alternative splicing is a cellular process and a primary source of proteome diversity. Switches in the Most Dominant Transcript (MDT), where the predominantly expressed isoform changes between normal and cancer samples, have been implicated in disrupting protein interaction networks and driving tumour progression. Thus, identifying switching events in MDT isoforms is crucial for discovering diagnostic biomarkers or therapeutic targets. Methods Here, we present the most comprehensive study on validated MDT-switching events in melanoma, ovarian cancer, and AML. Results We identified 6114 unique cancer-associated MDTs (cMDTs) across the three cancer types compared to corresponding normal tissue, of which 1707 cMDTs encode transmembrane proteins, and 131 occur at a high frequency (>30%) in at least one cancer cohort. We validated 12.1% of cMDTs using mass spectrometry-based proteomics data, such as the long isoform of ADD3, which we frequently found in ovarian cancer samples. Our analysis revealed that most of these cMDTs lose interactions with protein partners and drug compounds and correlate with switch events in the spliceosome. Conclusion This study identifies cMDTs that may serve as candidate biomarkers in melanoma, ovarian cancer, and AML, with the potential to improve cancer diagnosis and support clinical decision-making.