---
title: "Cancer-associated isoform switches reshape protein and drug interactions in melanoma, ovarian canc"
id: "british-journal-of-cancer-1-switches-in-alternatively-spliced-isoforms-impact-protein-and-drug-interactions"
canonical_url: "https://medichelpline.com/clinical-feed/british-journal-of-cancer-1-switches-in-alternatively-spliced-isoforms-impact-protein-and-drug-interactions"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "British Journal of Cancer"
source_url: "https://www.nature.com/articles/s41416-026-03638-0"
published_at: "2026-10-03T12:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Cancer-associated isoform switches reshape protein and drug interactions in melanoma, ovarian canc
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/british-journal-of-cancer-1-switches-in-alternatively-spliced-isoforms-impact-protein-and-drug-interactions
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** British Journal of Cancer
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/s41416-026-03638-0)
- **Published At:** 2026-10-03T12:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Alternative splicing is a major source of proteome diversity and can produce isoform switches that alter protein structure, interactions, and function. - The study focused on switches in the **Most Dominant Transcript (MDT)** between normal and tumour samples as candidate drivers of tumour progression and biomarkers. - The authors analysed data from TCGA, GTEx and the Tumour Profiler (TuPro) project to characterise MDT switching in metastatic melanoma, ovarian cancer and acute myeloid leukaemia (AML). - Across the three cancer types they identified 6,114 unique **cancer-associated MDTs (cMDTs)** compared with matched normal tissues; 1,707 cMDTs encode transmembrane proteins. - Of the cMDTs, 131 occurred at high frequency (>30%) in at least one cancer cohort. - Mass spectrometry-based **proteomics** validated 12.1% of cMDTs, including recurring detection of the long isoform of ADD3 in ovarian cancer samples. - Most cMDTs showed loss of interactions with protein partners and with drug compounds when modelled in isoform-specific interaction networks. - cMDT occurrence correlated with switch events in the **spliceosome**, consistent with splicing dysregulation contributing to isoform switching. - The findings nominate isoform-specific RNA and protein candidates for diagnostic biomarkers and highlight potential impacts on drug response and clinical decision-making. - The source report provides methods for RNA-Seq processing and multi-omics integration but the provided text is incomplete in places (for example, the TuPro cohort description and some methods are truncated), so some procedural details and full results were not reported in the source excerpt.
## Clinical Analysis & Structured Key Points
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[nature](https://www.nature.com/) 2. [british journal of cancer](https://www.nature.com/bjc) 3. [articles](https://www.nature.com/bjc/articles?type=article) 4. article Switches in alternatively spliced isoforms impact protein and drug interactions in melanoma, ovarian cancer, and acute myeloid leukemia [ Download PDF ](https://www.nature.com/articles/s41416-026-03638-0.pdf) [ Download PDF ](https://www.nature.com/articles/s41416-026-03638-0.pdf) * Article * [Open access](https://www.springernature.com/gp/open-science/about/the-fundamentals-of-open-access-and-open-research) * Published: 03 October 2026 Genetics and Genomics # Switches in alternatively spliced isoforms impact protein and drug interactions in melanoma, ovarian cancer, and acute myeloid leukemia * [Tülay Karakulak](https://www.nature.com/articles/s41416-026-03638-0#auth-T_lay-Karakulak-Aff1-Aff2-Aff3)[1](https://www.nature.com/articles/s41416-026-03638-0#Aff1),[2](https://www.nature.com/articles/s41416-026-03638-0#Aff2),[3](https://www.nature.com/articles/s41416-026-03638-0#Aff3), * [Tumor Profiler Consortium](https://www.nature.com/articles/s41416-026-03638-0#group-1), * [Holger Moch](https://www.nature.com/articles/s41416-026-03638-0#auth-Holger-Moch-Aff2-Aff4)[2](https://www.nature.com/articles/s41416-026-03638-0#Aff2),[4](https://www.nature.com/articles/s41416-026-03638-0#Aff4), * [Christian von Mering](https://www.nature.com/articles/s41416-026-03638-0#auth-Christian-Mering-Aff1-Aff3)[1](https://www.nature.com/articles/s41416-026-03638-0#Aff1),[3](https://www.nature.com/articles/s41416-026-03638-0#Aff3) & * … * [Abdullah Kahraman](https://www.nature.com/articles/s41416-026-03638-0#auth-Abdullah-Kahraman-Aff3-Aff5-Aff6) [ORCID: orcid.org/0000-0003-3523-4467](https://orcid.org/0000-0003-3523-4467)[3](https://www.nature.com/articles/s41416-026-03638-0#Aff3),[5](https://www.nature.com/articles/s41416-026-03638-0#Aff5),[6](https://www.nature.com/articles/s41416-026-03638-0#Aff6) Show authors [_British Journal of Cancer_](https://www.nature.com/bjc) (2026) [Cite this article](https://www.nature.com/articles/s41416-026-03638-0#citeas) [ Save article ](https://www.nature.com/articles/s41416-026-03638-0/save-research?_csrf=PkN4hdz2JmjqR0A02FHi9x11YExF2tt1) [ View saved research ](https://www.nature.com/saved-research) ## 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. ### Explore related subjects Discover the latest articles and news in related subjects. * [Cancer genomics](https://www.nature.com/subjects/cancer-genomics) * [Computational biology and bioinformatics](https://www.nature.com/subjects/computational-biology-and-bioinformatics) * [Tumour biomarkers](https://www.nature.com/subjects/tumour-biomarkers) ## Introduction In eukaryotes, splicing removes introns from pre-mRNA and long non-coding RNA molecules, while exons are preserved in the mature RNA molecule. Variations in this process (Alternative Splicing, AS) produce multiple RNA variants from a given gene locus, increasing proteome complexity [[1](https://www.nature.com/articles/s41416-026-03638-0#ref-CR1 "Marasco LE, Kornblihtt AR. The physiology of alternative splicing. Nat Rev Mol Cell Biol. 2023;24:242–54. https://doi.org/10.1038/s41580-022-00545-z .")]. AS might be modulated in a tissue- or organ-specific manner. Changes in AS have been shown to correlate with body temperature or circadian rhythm [[1](https://www.nature.com/articles/s41416-026-03638-0#ref-CR1 "Marasco LE, Kornblihtt AR. The physiology of alternative splicing. Nat Rev Mol Cell Biol. 2023;24:242–54. https://doi.org/10.1038/s41580-022-00545-z .")]. Spliced isoforms can have different protein structures or folding, affecting their function by rewiring interactions with other molecules, such as proteins or nucleic acids, with or without changing their interaction sites [[2](https://www.nature.com/articles/s41416-026-03638-0#ref-CR2 "Kjer-Hansen P, Weatheritt RJ. The function of alternative splicing in the proteome: rewiring protein interactomes to put old functions into new contexts. Nat Struct Mol Biol. 2023;30:1844–56. https://doi.org/10.1038/s41594-023-01155-9 .")]. AS switching events can result from mutations in splicing machinery genes, expression changes in associated proteins [[3](https://www.nature.com/articles/s41416-026-03638-0#ref-CR3 "Anczuków O, Krainer AR. Splicing-factor alterations in cancers. RNA. 2016;22:1285–301. https://doi.org/10.1261/rna.057919.116 .")], or mutations in splice junctions and regions [[4](https://www.nature.com/articles/s41416-026-03638-0#ref-CR4 "Karakulak T, Moch H, Von Mering C, Kahraman A. Probing isoform switching events in various cancer types: lessons from pan-cancer studies. Front Mol Biosci. 2021;8:726902. https://doi.org/10.3389/fmolb.2021.726902 .")]. The switch between canonical and alternative isoforms within a cell or tissue has sometimes been shown to drive tumour progression and predict overall survival across multiple cancers. The role of AS and its dysregulation in cancer has been extensively reviewed before [[5](https://www.nature.com/articles/s41416-026-03638-0#ref-CR5 "Bonnal SC, López-Oreja I, Valcárcel J. Roles and mechanisms of alternative splicing in cancer — implications for care. Nat Rev Clin Oncol. 2020;17:457–74. https://doi.org/10.1038/s41571-020-0350-x ."),[6](https://www.nature.com/articles/s41416-026-03638-0#ref-CR6 "Bradley RK, Anczuków O. RNA splicing dysregulation and the hallmarks of cancer. Nat Rev Cancer. 2023;23:135–55. https://doi.org/10.1038/s41568-022-00541-7 ."),[7](https://www.nature.com/articles/s41416-026-03638-0#ref-CR7 "Zhang Y, Qian J, Gu C, Yang Y. Alternative splicing and cancer: a systematic review. Signal Transduct Target Ther. 2021;6:78 https://doi.org/10.1038/s41392-021-00486-7 .")]. For example, SF3B4, a splicing factor, is upregulated in ovarian cancer, where it promotes efficient splicing of intron 8 in the DNA damage repair factor RAD52, yielding functional RAD52 protein and contributing to cancer progression. Loss of SF3B4 causes intron 8 retention, generating a premature termination codon and a non-productive transcript [[8](https://www.nature.com/articles/s41416-026-03638-0#ref-CR8 "Diao Y, Li Y, Wang Z, Wang S, Li P, Kong B. SF3B4 promotes ovarian cancer progression by regulating alternative splicing of RAD52. Cell Death Dis. 2022;13:179. https://doi.org/10.1038/s41419-022-04630-1 .")]. Alternative splicing also has a role in drug resistance and treatment outcomes. The best-known example in cutaneous melanoma is the BRAF V600E splice variant [[9](https://www.nature.com/articles/s41416-026-03638-0#ref-CR9 "Vido MJ, Le K, Hartsough EJ, Aplin AE. BRAF splice variant resistance to RAF inhibitor requires enhanced MEK association. Cell Rep. 2018;25:1501–1510.e3. https://doi.org/10.1016/j.celrep.2018.10.049 ."),[10](https://www.nature.com/articles/s41416-026-03638-0#ref-CR10 "Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF\(V600E\). Nature. 2011;480:387–90. https://doi.org/10.1038/nature10662 ."),[11](https://www.nature.com/articles/s41416-026-03638-0#ref-CR11 "Basile KJ, Abel EV, Dadpey N, Hartsough EJ, Fortina P, Aplin AE. In vivo MAPK reporting reveals the heterogeneity in tumoral selection of resistance to RAF inhibitors. Cancer Res. 2013;73:7101–10. https://doi.org/10.1158/0008-5472.CAN-13-1628 .")]. One mechanism by which patients develop resistance to RAF inhibitors is by increasing the expression of BRAF splice variants. A point mutation in intron 8 causes the skipping of exons 4-8, generating BRAF isoforms that lack the RAS binding domain, which causes dimerizations at low RAS levels and resistance to the FDA-approved RAF inhibitor vemurafenib [[12](https://www.nature.com/articles/s41416-026-03638-0#ref-CR12 "Salton M, Kasprzak WK, Voss T, Shapiro BA, Poulikakos PI, Misteli T. Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing. Nat Commun. 2015;6:7103. https://doi.org/10.1038/ncomms8103 .")]. In melanoma, elevated pretreatment levels of soluble splicing variants of Programmed death-ligand 1 (sPD-L1) have been associated with an increased chance of progressive disease during immune checkpoint blockade therapies [[13](https://www.nature.com/articles/s41416-026-03638-0#ref-CR13 "Zhou J, Mahoney KM, Giobbie-Hurder A, Zhao F, Lee S, Liao X, et al. Soluble PD-L1 as a biomarker in malignant melanoma treated with checkpoint blockade. Cancer Immunol Res. 2017;5:480–92. https://doi.org/10.1158/2326-6066.CIR-16-0329 .")]. The role of AS has also been shown in blood and bone marrow cancers, including Acute Myeloid Leukemia (AML). For example, an alternative transcript of DExD/H-box RNA helicase (DHX34) [[14](https://www.nature.com/articles/s41416-026-03638-0#ref-CR14 "Rivera OD, Mallory MJ, Quesnel-Vallières M, Chatrikhi R, Schultz DC, Carroll M, et al. Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia. Proc Natl Acad Sci USA. 2021;118:e2014967118. https://doi.org/10.1073/pnas.2014967118 .")], a nonsense-mediated decay factor [[15](https://www.nature.com/articles/s41416-026-03638-0#ref-CR15 "Hug N, Cáceres JF. The RNA helicase DHX34 activates NMD by promoting a transition from the surveillance to the decay-inducing complex. Cell Rep. 2014;8:1845–56. https://doi.org/10.1016/j.celrep.2014.08.020 .")] that also associates with the spliceosome complex [[17](https://www.nature.com/articles/s41416-026-03638-0#ref-CR17 "Ammar C, Csaba G, Hadziahmetovic A, Vasilopoulou CG, Gruber M, Mann M, et al. Detecting differential alternative splicing in mass spectrometry-based proteomics data. 2023. Available from: http://biorxiv.org/lookup/doi/10.1101/2023.09.19.558203 ")], reduces the expression of full-length DHX34. This loss of DHX34 disrupts differentiation of erythroid and myeloid lineages [[16](https://www.nature.com/articles/s41416-026-03638-0#ref-CR16 "Hug N, Aitken S, Longman D, Raab M, Armes H, Mann AR, et al. A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its function in hematopoietic differentiation. RNA. 2022;28:1224–38. https://doi.org/10.1261/rna.079277.122 .")]. Thus, dissecting a patient’s splicing profile can be paramount in selecting suitable treatment options and predicting treatment outcomes. Validating spliced isoform expression at the protein level requires advanced techniques such as mass spectrometry or ribosome profiling. Previous studies have successfully identified spliced isoforms across different tissues [[17](https://www.nature.com/articles/s41416-026-03638-0#ref-CR17 "Ammar C, Csaba G, Hadziahmetovic A, Vasilopoulou CG, Gruber M, Mann M, et al. Detecting differential alternative splicing in mass spectrometry-based proteomics data. 2023. Available from: http://biorxiv.org/lookup/doi/10.1101/2023.09.19.558203 "),[18](https://www.nature.com/articles/s41416-026-03638-0#ref-CR18 "Weatheritt RJ, Sterne-Weiler T, Blencowe BJ. The ribosome-engaged landscape of alternative splicing. Nat Struct Mol Biol. 2016;23:1117–23. https://doi.org/10.1038/nsmb.3317 ."),[19](https://www.nature.com/articles/s41416-026-03638-0#ref-CR19 "Zhang F, Deng CK, Wang M, Deng B, Barber R, Huang G. Identification of novel alternative splicing biomarkers for breast cancer with LC/MS/MS and RNA-Seq. BMC Bioinform. 2020;21:541. https://doi.org/10.1186/s12859-020-03824-8 ."),[20](https://www.nature.com/articles/s41416-026-03638-0#ref-CR20 "Sheynkman GM, Shortreed MR, Frey BL, Smith LM. Discovery and mass spectrometric analysis of novel splice-junction peptides using RNA-Seq. Mol Cell Proteomics. 2013;12:2341–53. https://doi.org/10.1074/mcp.O113.028142 .")]. The Tumour Profiler (TuPro) Project is a multi-omics study of ovarian cancer, metastatic melanoma, and AML with matched RNA-seq and Proteomics datasets, providing a unique resource to validate identified cMDTs [[21](https://www.nature.com/articles/s41416-026-03638-0#ref-CR21 "Irmisch A, Bonilla X, Chevrier S, Lehmann KV, Singer F, Toussaint NC, et al. The Tumor Profiler Study: integrated, multi-omic, functional tumor profiling for clinical decision support. Cancer Cell. 2021;39:288–93. https://doi.org/10.1016/j.ccell.2021.01.004 .")]. Here, we aimed to investigate the AS profile of 170 patients suffering from metastatic melanoma, ovarian cancer, and AML within TuPro. We integrated multi-omics-level data from TCGA. Proteomics data were used to validate cMDTs. To assess the functional impact of cMDTs, we developed isoform-specific protein-protein and protein-drug interaction networks. Our study lists potential isoform-specific diagnostic biomarkers at the RNA and protein levels that indicate ovarian cancer, melanoma, and AML. ## Methods ### Bulk RNA-Seq data processing After applying for access to the raw RNA-Seq data from GTEx (RRID: SCR_013042) and TCGA (RRID: SCR_003193), we downloaded raw 112 Ovary and 273 Skin GTEx bulk RNA-Seq samples from the Genotypes and Phenotypes (dbGaP) database using sra-toolkit (RRID: SCR_024350). GTEx does not include bone marrow tissue samples, so we downloaded 465 blood samples for comparison with AML. Raw bulk TCGA RNA-Seq samples (381 TCGA-OV, 473 TCGA-SKCM (Skin part without Sun exposure), 129 TCGA-LAML (Primary Blood-Derived Cancer - Peripheral Blood) samples) were downloaded from the Genomic Data Common Data Portal (GDC Data Portal) using the GDC Data Transfer Tool (RRID: SCR_014514) (Fig. [1](https://www.nature.com/articles/s41416-026-03638-0#Fig1)). The TuPro study includes 43 ovarian cancer cases, 83 metastatic melanoma (cutaneous melanoma with st
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