Anatomical and clinical heterogeneity of dMMR colorectal cancer by tumor location.

e15725 Background: Deficient mismatch repair (dMMR) colorectal cancer is a biologically heterogeneous disease. Tumors from different anatomical sites arise from distinct embryonic layers and show variable clinical behavior, including differing responses to immunotherapy. However, large-scale studies systematically examining how tumor location influences dMMR patterns and associated clinicopathologic features remain limited. Methods: We retrospectively analyzed 1,021 patients with dMMR colorectal cancer confirmed by immunohistochemistry. Tumors were classified by location (right-sided colon, left-sided colon, rectum) and by dMMR pattern (MLH1/PMS2 loss, MSH2/MSH6 loss, isolated PMS2 loss, isolated MSH6 loss, and others. Clinicopathologic features were compared across locations and patterns using univariate and multivariable analyses. Results: Significant differences in dMMR patterns were observed across anatomical sites (P < 0.001). Right clon were predominantly MLH1/PMS2 loss (67.9%), while rectal showed higher prevalence of isolated PMS2 loss (30.9%). Left colon were more frequently associated with MSH2/MSH6 and isolated MSH6 loss. Clinically, right colon was characterized by larger diameters (P = 0.006), whereas rectal was significantly associated with younger age (P = 0.001), male sex (P = 0.034), and higher Ki-67 expression (P = 0.05). Multivariable analysis confirmed that dMMR subtype is an independent predictor of tumor location, specifically with MLH1/PMS2 loss strongly associated with right colon cancer. Conclusions: Our findings highlight the significant anatomical and clinicopathologic heterogeneity within dMMR colorectal cancer. These site-specific differences in dMMR subtypes and tumor aggressiveness may stem from distinct embryological origins. Consequently, dMMR alone is insufficient for clinical stratification; anatomical location and specific deficiency subtypes must be integrated to enable precise risk assessment and individualized therapeutic decision-making. Multivariable analysis of clinicopathologic factors associated with tumor location in dmmr colorectal cancer. Variable Right Colon VS Left Colon OR (95% Cl) P-value Rectum VS Left Colon OR (95% Cl) P-value Age (＜65 VS ≥65) 0.719 (0.444,1.163) 0.179 0.413 (0.247,0.691) 0.001 Sex (Male VS Female) 0.788 (0.489,1.268) 0.325 1.752 (1.043,2.942) 0.034 Maximum tumor diameter 1.164 (1.045,1.296) 0.006 0.794 (0.702,0.898) 0.000 Perineural Invasion (No VS Yes) 1.144 (0.446,2.932) 0.779 0.269 (0.112,0.651) 0.004 Ki-67 (Low VS High) 0.803 (0.260,2.481) 0.704 2.910 (0.998,8.485) 0.050 dMMR: MLH1/PMS2 loss (ref Other)dMMR: MSH2/MSH6 loss (ref Other)dMMR: MSH6 loss (ref Other)dMMR: PMS2 loss (ref Other) 3.765 (1.842,7.697)1.803 (0.761,4.274)0.805 (0.331,1.961)1.084 (0.443,2.654) 0.0000.1810.6330.859 0.810 (0.387,1.696)0.928 (0.382,2.253)0.628 (0.260,1.522)1.777 (0.772,4.087) 0.5760.8690.3030.176