Mismatch Repair Pathway, MLH1, MSH2 and Mutations in Prostate Cancer

ObjectivesThe DNA mismatch repair (MMR) pathway preserves genomic stability by correcting replication errors, with MLH1 and MSH2 playing central roles in mismatch recognition and repair. Loss of these proteins results in microsatellite instability, increased mutational burden, and genomic instability, contributing to prostate cancer development and progression. Emerging evidence suggests that MMR alterations define a distinct and clinically relevant subset of prostate cancer.MethodsA narrative literature review was performed using PubMed, Scopus, and Google Scholar databases. Articles published in English up to January 2026 were screened using combinations of the keywords "prostate cancer," "mismatch repair," "MLH1," "MSH2," "microsatellite instability," and "DNA repair." Original studies, clinical trials, genomic analyses and relevant review articles focusing on MMR alterations in prostate cancer were included.ResultsGermline MMR mutations are uncommon in prostate cancer; however, somatic alterations, particularly involving MSH2 and less frequently MLH1, are enriched in advanced and metastatic disease. MMR-deficient tumors demonstrate high tumor mutational burden, increased neoantigen formation, enhanced immune infiltration, and upregulation of immune checkpoint molecules such as PD-L1, contributing to responsiveness to immunotherapy.ConclusionMLH1 and MSH2 alterations define a clinically significant molecular subtype of prostate cancer. Identification of MMR deficiency can guide immunotherapy selection, supporting the integration of molecular profiling into routine clinical practice.