Mismatch Repair Deficiency Is a Prognostic Factor Predicting Good Survival of Opisthorchis viverrini-Associated Cholangiocarcinoma at Early Cancer Stage

SIMPLE SUMMARY: The mismatch repair (MMR) system prevents DNA mutations, and deficient MMR protein (dMMR) can lead to genetic changes and microsatellite instability (MSI). While dMMR is typically associated with positive outcomes in various cancers, its role in cholangiocarcinoma (CCA) remains uncertain. This study’s objective was to assess the prevalence of dMMR in CCA patients and examine its relationship with clinicopathological features and patient survival following surgery. This study showed that dMMR was present in 22.5% of CCA patients and was associated with better survival, especially in early-stage CCA and when combined with adjuvant chemotherapy. This study suggests that dMMR could be a valuable marker for selecting CCA patients for specific adjuvant treatments after surgery. ABSTRACT: Background: The mismatch repair (MMR) system prevents DNA mutation; therefore, deficient MMR protein (dMMR) expression causes genetic alterations and microsatellite instability (MSI). dMMR is correlated with a good outcome and treatment response in various cancers; however, the situation remains ambiguous in cholangiocarcinoma (CCA). This study aims to evaluate the prevalence of dMMR and investigate the correlation with clinicopathological features and the survival of CCA patients after resection. Materials and Methods: Serum and tissues were collected from CCA patients who underwent resection from January 2005 to December 2017. Serum OV IgG was examined using ELISA. The expression of MMR proteins MLH1, MSH2, MSH6 and PMS2 was investigated by immunohistochemistry; subsequently, MMR assessment was evaluated as either proficient or as deficient by pathologists. The clinicopathological features and MMR status were compared using the Chi-square test. Univariate and multivariate analyses were conducted to identify prognostic factors. Results: Among the 102 CCA patients, dMMR was detected in 22.5%. Survival analysis revealed that dMMR patients had better survival than pMMR (HR = 0.50, p = 0.008). In multivariate analysis, dMMR was an independent factor for a good prognosis in CCA patients (HR = 0.58, p = 0.041), especially at an early stage (HR = 0.18, p = 0.027). Moreover, subgroup analysis showed dMMR patients who received adjuvant chemotherapy had better survival than surgery alone (HR = 0.28, p = 0.012). Conclusion: This study showed a high prevalence of dMMR in cholangiocarcinoma with dMMR being the independent prognostic factor for good survival, especially in early-stage CCA and for patients who received adjuvant chemotherapy. dMMR should be the marker for selecting patients to receive a specific adjuvant treatment after resection for CCA.