Research report: Differential MMR protein stability and heterogeneity in bladder versus non-bladder urothelial carcinomas

Mismatch repair deficiency was absent in all 72 bladder urothelial carcinoma cases analyzed in a cohort of 108 patients, and its status remained consistent across multiple specimens from every bladder patient who contributed more than one sample. In contrast, deficiency occurred in two of 35 upper-tract urothelial carcinomas and the single prostatic urothelial carcinoma included in the study. Among the few deficient non-bladder cases, some primary and metastatic lesions showed divergent mismatch repair status, indicating that biomarker results could differ between sampled tumors in the same patient.

For a subset of patients, investigators obtained multiple samples spanning primary tumors, locally invasive disease, metastases and recurrent tumors. This spatiotemporal collection permitted comparison of mismatch repair status not only between anatomic sites but also across stages and recurrences within individual patients. Investigators assessed expression of four mismatch repair proteins—MLH1, MSH2, MSH6 and PMS2—by immunohistochemistry.

All 72 bladder urothelial carcinoma cases were classified as proficient, and results were 100% concordant across the paired primary, locally invasive, metastatic or recurrent specimens examined from bladder patients. The non-bladder group produced a different but numerically limited pattern: two of 35 upper-tract cases were deficient, as was the one prostatic case. Within the small set of deficient non-bladder tumors, the researchers observed examples in which primary and metastatic lesions had divergent statuses.

The findings suggest a potential site-specific dichotomy in the stability of mismatch repair deficiency in urothelial carcinoma. Bladder tumors in this cohort combined a very low observed frequency of deficiency with stable classification across available longitudinal and metastatic samples, while the limited deficient non-bladder cases included discordant results between lesions. Because only three non-bladder cases were deficient, however, the authors describe the pattern as hypothesis-generating rather than conclusive.

The study does not establish how often mismatch repair status changes in non-bladder disease, why discordance occurred, or whether sampling additional lesions would affect clinical decisions. Validation in larger, independent cohorts would be required to assess the reproducibility and scope of the observed contrast. The results also do not directly demonstrate differences in immunotherapy response; they concern the detection and stability of a biomarker used to predict response in various cancers.

Subject of Research: Mismatch repair protein stability in bladder and non-bladder urothelial carcinoma

Article Title: Differential MMR protein stability and heterogeneity in bladder versus non-bladder urothelial carcinomas

Article References: Chen, H., Zhong, M., Zhang, T., Wen, Z., Zheng, Z., Chen, J., Feng, Y., & Zhu, J. (2026). Differential MMR protein stability and heterogeneity in bladder versus non-bladder urothelial carcinomas. BMC Cancer. https://doi.org/10.1186/s12885-026-16867-6

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16867-6

Keywords: urothelial carcinoma, bladder cancer, mismatch repair, dMMR, MLH1, MSH2, MSH6, PMS2, immunohistochemistry, biomarker stability, Differential, protein