The effect of mismatch repair genes on prognosis in colorectal cancers

This study aimed to retrospectively evaluate the effects of mismatch repair genes (MLH1, MSH2, MSH6, PMS2) on survival and clinical parameters in patients with colorectal cancer. This is a retrospective cross-sectional analysis conducted in the general surgery clinic of a university hospital between 2016 and 2021. Data from 230 colorectal cancer patients were examined. Pathological parameters such as tumor location, preoperative metastasis, neoadjuvant and adjuvant treatments, tumor histology, size, lymph node and perineural invasion, and immunohistochemical (IHC) staining results for MSH2, MSH6, PMS2, and MLH1 proteins were evaluated. These 44 patients with microsatellite instability (MSI-dMMR), who were the focus of the study, were designated Group 1 (MSI group). The 186 patients with stable microsatellite (MSS-pMMR) genes, with whom the data would be compared and who constituted the majority of the population, were designated Group 2. The mean age of the patients was 61.52 years in the MSI group and 62.6 years in the MSS group. 65.9% of the MSI group and 55.9% of the MSS group were male. In the MSI group, 63.6% of the patients underwent right hemicolectomy. In the MSS group, 33.9% underwent low anterior resection and 30.1% underwent anterior resection/transverse colectomy. The most common tumor location in the MSI group was the cecum (34.1%), and in the MSS group, the most common tumor location was the sigmoid colon (40.3%). Preoperative metastases were present in 31.8% of the MSI group and 32.3% of the MSS group. The most common sites of metastasis are the liver and lymph nodes. Neoadjuvant therapy constituted 22.7% of MSI and 33.3% of MSS patients, and a combination of capecitabine, oxaliplatin, and radiotherapy was the preferred treatment in both groups. The most common tumor type was differentiated tumors, accounting for 81.8% of MSI and 91.5% of MSS patients. The most common tumor stage was T3 (MSI=52.3%/MSS=48.9). Lymph node metastasis was not observed in the majority of cases (N0, MSI=72.7%/MSS=54.8). Lymphovascular embolism was positive in 16 (36.4%) of MSI and 58 (31.2%) of MSS patients. The loss rates for the Mismatch Repair (MMR) proteins MSH6 (38.6%), MLH1 (61.4%), and PMS2 (68.2%) in MSI were notable. A significant difference was found in lymph node metastasis (N stage) in MSI (p=0.028) and MSS (p=0.008). In both groups, a comparison of surviving and exitus patients revealed no statistically significant difference in tumor size (T stage). The presence of lymphovascular embolism (LVE) in MSI was observed in 33.3% of the survivors and 42.9% of the exitus group; however, this difference was not statistically significant (p=0.388). The presence of lymphovascular embolism (LVE) in MSS was observed in 23.9% of the survivors and 42.5% of the exitus group, and this difference was statistically significant (p=0.006). A significant difference was found between surviving and exitus patients in terms of perineural invasion (PNI) in both groups. Survival analysis revealed a median survival of 21 (95% CI: 5.7-36.3) months in the MSI group and 24 (95% CI: 17.1-30.9) months in the MSS group, with the difference being insignificant. When other parameters that may impact survival (age and metastatic disease status at diagnosis) were evaluated in multivariate analysis along with MSI, the presence of metastatic disease was found to have a significant impact on survival, independent of age and MSI status (OR: 0.465, 95% CI: 0.291-0.742, p=0.001). This suggests a significant relationship between MSI status and tumor biology, and this distinction may be important in determining therapeutic strategies. Given the potential benefit of immunotherapeutic approaches, particularly in MSI-positive patients, it is recommended that all colorectal cancer patients be evaluated for MMR status. Furthermore, microsatellite analysis is an important biomarker for understanding heterogeneity in colorectal cancer, and considering this parameter in diagnostic, therapeutic, and follow-up algorithms will significantly contribute to clinical practice. MSI status has no impact on overall survival. The presence of metastatic disease at diagnosis has an impact on survival independent of other parameters.