Tropomyosin Isoforms as Biomarkers for Urothelial Bladder Cancer: Promise and Challenges

Tropomyosin (TPM) isoforms have been proposed as potential non-invasive biomarkers for urothelial bladder cancer (UBC) owing to their altered expression in tumors and detectability in urine. Some transcriptomic studies have reported a high diagnostic accuracy of approximately 0.85 area under the curve (AUC) for TPM1-3 as a standard in distinguishing UBC from normal tissue. However, critical evaluation has revealed several limitations, including insufficient clinical validation, isoform complexity, non-specific expression across cancer types, lack of mechanistic insights, and challenges in urinary detection. Current evidence regarding TPM relies largely on retrospective bioinformatics analyses of tumor RNA, such as The Cancer Genome Atlas (TCGA), rather than validated clinical assays, raising concerns about generalizability. The TPM family is highly complex (four genes, >40 splice isoforms) with tissue-specific expression, and similar dysregulation occurs in other cancers, undermining its specificity for UBC. Crucially, no established assays exist for isoform-specific TPMs in urine, and urinary proteins can degrade if the samples are not handled properly. Therefore, although the findings are promising in concept, TPM isoforms lack rigorous clinical validation and technical feasibility to serve as standalone UBC biomarkers. This review systematically examines these concerns, highlighting the need for comprehensive research before TPM isoforms can be reliably employed as clinical biomarkers for UBC.