Prevalence and Immunohistochemical Patterns of Mismatch Repair Deficiency in Colorectal Adenocarcinoma: A Retrospective Cross-Sectional Study from Northwestern Iran

Abstract

Background: Deficient mismatch repair in colorectal adenocarcinoma is a clinically relevant biomarker for Lynch syndrome screening, prognostic assessment, and therapeutic stratification. However, regional data on the prevalence of dMMR and immunohistochemical patterns of protein loss remain limited in Iran. Objectives: This study aimed to determine the prevalence of dMMR and to characterize mismatch repair (MMR) protein loss patterns in a colorectal cancer cohort in Northwestern Iran. Methods: In this retrospective cross-sectional study, we analyzed consecutive colorectal cancer cases using immunohistochemistry (IHC) for MLH1, PMS2, MSH2, and MSH6. Deficient MMR was defined as the loss of nuclear expression of at least 1 MMR protein in tumor cells, with retained staining in internal control cells. We assessed the prevalence of dMMR and the distribution of MMR protein loss patterns. Results: Overall, 103 of 853 patients had dMMR, yielding a prevalence of 12.1% (95% confidence interval [CI], 10.1%–14.4%). The prevalence of dMMR was higher in 2023 than in 2024 (57/352 [16.2%] vs. 46/501 [9.2%]; P = 0.003). Diagnosis year remained associated with dMMR status after adjustment for age and sex (odds ratio [OR] for 2024 vs. 2023, 0.52; 95% CI, 0.34 - 0.79; P = 0.002), whereas age and sex were not significantly associated with dMMR status. Among dMMR tumors, combined MLH1/PMS2 loss (35.0%) and isolated PMS2 loss (30.1%) were the most frequent protein-loss patterns. Conclusions: In this Northwestern Iranian cohort, dMMR was identified in approximately 1 in 8 cases of colorectal adenocarcinoma, consistent with international prevalence estimates. The relatively high frequency of isolated PMS2 loss underscores the need for careful technical interpretation and future molecular validation to clarify its biological and diagnostic significance.