Mutation profile and molecular heterogeneity in mismatch repair deficient endometrial carcinoma

Abstract Endometrial carcinoma (EC) with deficient DNA mismatch repair (dMMR) is a specific molecular entity with unique clinicopathological features. Herein, we depicted the mutation profile of dMMR ECs and explored the molecular heterogeneity among dMMR subgroups with different etiologies. Next-generation sequencing based on a 1021-gene panel was applied to 74 dMMR ECs and 43 proficient MMR (pMMR) ECs. In addition, methylation-specific PCR was applied for accessing MLH1 promoter hypermethylation (MLH1me+) in dMMR cases. The mutation rates of PTEN, ARID1A, KRAS, and MSH2 were significantly higher in dMMR group, while the CTNNB1 and MSH3 mutations were more commonly observed in pMMR group (p CTNNB1 mutation were found in dMMR ECs, while half of the WNT-activated pMMR ECs were CTNNB1 mutated, which were generally mutually exclusive with other WNT pathway key genes. The median tumor mutational burden (TMB) of dMMR ECs was significantly higher than pMMR ECs. However, ultra-high TMB value was related to pathogenic POLE mutation both in dMMR and pMMR ECs. As for dMMR subgroups, KEAP1 and FBXW7 mutations, which may have potential predictive effect of immunotherapy, were more prevalent in the Lynch subgroup. The Lynch subgroup also had significantly higher median TMB than the MLH1me+ subgroup and Lynch-like subgroup. dMMR ECs has distinctive genomic profile with molecular heterogeneity, which may have potential prognostic and therapeutic implications.