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

Abstract 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.

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Publication Details

Journal
British Journal of Cancer
Published
2026-10-03
DOI
https://doi.org/10.1038/s41416-026-03638-0
Primary Topic
RNA Research and Splicing
Type
article
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article

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

René Holtackers, Viktor Hendrik Koelzer, Laurie Prélot, Marina Bacac et al.
British Journal of Cancer
RNA Research and Splicing
article

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

René Holtackers, Viktor Hendrik Koelzer, Laurie Prélot, Marina Bacac, Jonas Albinus, María Lourdes Rosano-González, André Fedier, Franziska Singer, Stefanie Engler, Ricardo Coelho, Sylvia Herter, Bernd Bodenmiller, Lars Bosshard, Linda Grob, Natalia Chicherova, Daniel Baumhoer, Tobias Schär, Beatrice Beck‐Schimmer, Gabriela Senti, Stefan Nicolet, Petra Catalina Schwalie, Christian P. Kunze, Kjong-Van Lehmann, Martin Mehnert, Silvana Iuliana Albert, Cinzia Esposito, Sonali Andani, Lara Bernasconi, Flavio C. Lombardo, Katja Eschbach, Lucas Pelkmans, Martin Erkens, Severin Schwan, Detlef Günther, Melike Ak, Nicola Miglino, Gunnar Rätsch, Niko Beerenwinkel, Michael Prummer, Sandra Goetze, Jack Kuipers, Esther Danenberg, Ruben Casanova, Francis Jacob, Per-Olof Attinger, Julian Matthias Metzler, Tamara Huesser, Gabriele Gut, Ximena Bonilla, Wenguang Shao, Tülay Karakulak, Salvatore Piscuoglio, Ilaria Alborelli, Simone E. Muenst, Mónica Núñez López, Christian Beisel, Viola A Heinzelmann-Schwarz, Rudolf Aebersold, Ramona Schlenker, Anne Bertolini, Christian Rommel, Maya D’Costa, Alva Rani James, Ulrike Lischetti, Anja Irmisch, Werner Kuebler, Stéphane Chevrier, André Kahles, Philip M. Jermann, Emanuela S. Milani, Natascha Santacroce, Julien Mena, Pirmin Haeuptle, Jacobo Sarabia del Castillo, Sebastian Lugert, Natalie Rimmer, Monica-Andreea Baciu-Drăgan, Reinhard Dummer, Philipp Markolin, Christian Kurzeder, Byron Calgua, Joanna Ficek-Pascual, Marta Nowak, Katharina Jahn, Mitchell P. Levesque, Riccardo Murri, Alexander Immer, Gerd Maass, Tim M. Jaeger, Mathilde Ritter, Faisal S. Al-Quaddoomi, Andrea Jacobs, Pedro F. Ferreira, Natalie R. Davidson, Markus G. Manz, Anja L. Frei, Charlotte KY Ng, Patrick GA Pedriol, Bruno Frey, Abdullah Kahraman
article en

Abstract

Abstract 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.

British Journal of Cancer
Roche (Switzerland) (CH), University of Bern (CH), SIB Swiss Institute of Bioinformatics (CH), University of Basel (CH), University of Zurich (CH), University Hospital of Basel (CH), FHNW University of Applied Sciences and Arts Northwestern Switzerland (CH), ETH Zurich (CH), Kantonsspital Baselland (CH), Roche Pharma AG (Germany) (DE), University Hospital of Zurich (CH), Life Science Zurich (CH), Universitätsklinikum Aachen (DE), University Hospital Cologne (DE), NEXUS Personalized Health Technologies (CH), Institute for Molecular Systems Biology (CH), Institute for Machine Learning (CH), Institute of Molecular Health Sciences (CH), RWTH Aachen University (DE)
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RNA Research and Splicing
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