Characteristics of Mismatch Repair Deficient Colon Cancer in Relation to MMR Protein Loss, Hypermethylation Silencing, and Constitutional and Biallelic Somatic MMR Gene Pathogenic Variants

Mismatch repair deficient colon cancer is heterogeneous. Differentiating inherited constitutional variants from somatic genetic alterations and gene silencing is important for surveillance and genetic counseling.Determine the extent to which the underlying mechanism of loss of mismatch repair influences molecular and clinicopathologic features of microsatellite instability-high colon cancer.Retrospective analysis.Comprehensive cancer center.Patients with microsatellite instability-high colon cancer of stage I, II, or III.Curative surgical resection.Hypermethylation of the MLH1 promoter, biallelic inactivation, constitutional pathogenic variant, and loss of specific mismatch repair proteins.Of the 157 identified tumors with complete genetic analysis, 66% had hypermethylation of the MLH1 promoter, 18% had constitutional pathogenic variant (Lynch syndrome), 11% had biallelic somatic MMR gene pathogenic variants, and 6% had unexplained high microsatellite instability. The distribution of mismatch repair loss was as follows: MLH1 and PMS2 co-loss, 79% of the tumors; MSH2 and MSH6 co-loss, 10%; MSH6 alone, 3%; PMS2 alone, 2%; other combinations, 2%; no loss, 2%. Tumor mutational burden was lowest in MLH1- and PMS2-deficient tumors. MSH6-deficient tumors had the lowest levels of tumor-infiltrating lymphocytes, lowest MSIsensor scores, and fewest frameshift deletions. Patients with MLH1 promoter hypermethylation were significantly more likely to be older and female and to have right-colon lesions than patients with biallelic inactivation. Mutation was the most prevalent second hit in tumors with biallelic inactivation and tumors of patients with Lynch syndrome.Potential selection or referral bias, missing data for some patients, and relatively small sizes of some subgroups.Clinical characteristics of mismatch repair deficient colon cancer vary with the etiology of microsatellite instability, and its molecular characteristics vary with the affected mismatch repair protein. See Video Abstract at http://links.lww.com/DCR/B984.