Mismatch Repair Deficiency in Urothelial Carcinoma of the Bladder - Expert Commentary

Mutations in mismatch repair (MMR) genes result in changes in the expression of MMR proteins that can be detected by immunohistochemistry and high microsatellite instability (MSI). MSI-high tumors have higher rates of response to immune checkpoint inhibitors. Identifying these MSH-high tumors is essential for selecting patients who are likely to respond to immunotherapy.

A recent study published by Fraune et al. in Urologic Oncology examined the heterogeneity in MMR deficiency, MSI status, and confirmed MMR mutations of urothelial cancers. The authors analyzed the MLH1, PMS2, MSH2, and MSH6 protein expression in a tissue microarray (TMA) of 598 muscle-invasive urothelial carcinomas of the bladder. The study identified 9 cases suspicious for MSI, MMR status based on immunohistochemical analysis of the expression of MMR proteins. Following the examination of large sections for these and polymerase chain reaction (PCR)-based analysis of microsatellites using the Bethesda panel, the authors found that 4 cases were both MMR-deficient and MSI-high. One case was MMR deficient and MSI-high. Altogether, they reported that 5/448 interpretable cancers were validated, resulting in a prevalence of 1.1%. The authors used a sequencing panel targeting MLH1, MSH2, MSH6, PMS2 to identify mutations. An inactivating MLH1 mutation was identified in one tumor. 

The authors performed an extensive immunohistochemical analysis of all available 72 cancer-containing tissue blocks of the five confirmed bladder cancer with MSI, including prior and subsequent biopsies. Interestingly, this showed homogeneity of the MMR protein expression in longitudinally collected samples. Taken together, this data suggests that the MMR protein expression status of a biopsy is consistent throughout different regions of the tumor and is a stable feature acquired early during the evolution of the disease. However, because the correlation between MMR protein expression and MSI is imperfect, heterogeneity in MSI status between it remains to be seen whether urothelial cancers from the same patient consistently have concordant MSI status. 

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine


  1. Fraune C, Simon R, Hube-Magg C, Makrypidi-Fraune G, Kähler C, Kluth M, Höflmayer D, Büscheck F, Dum D, Luebke AM, Burandt E, Clauditz TS, Wilczak W, Sauter G, Steurer S. “MMR deficiency in urothelial carcinoma of the bladder presents with temporal and spatial homogeneity throughout the tumor mass.” Urol Oncol. 2020 Feb 14. pii: S1078-1439(19)30499-5. doi: 10.1016/j.urolonc.2019.12.012. [Epub ahead of print] PMID: 32067846
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