MLH1 promoter hypermethylation in mismatch repair deficient endometrial cancer.Defining a new subgroup?

Objective Nearly 30% of unselected endometrial cancer (EC) are mismatch repair deficient (MMRd).The majority resulting from epigenetic changes due to MLH1 promoter hypermethylation (MLH1-PM) and only a fraction from mutations in the Lynch genes (MLH1/MSH2/MSH6/PMS2).

Since less is known about the clinical characteristics of MMRd tumors especially based on MLH1-PM we aimed at clarifying the clinical features of EC with MLH1-PM.

Methods EC patients treated between 2015-2022 who underwent MMR(IHC) +/- MLH1-PM (PCR)-testing were included. Three groups where defined. A)MMR proficient(p) B) MMRd/MLH1-PM 3) “probable” Lynch (defined as MMRd not due to MLH1-PM).

Results MMR-testing was performed in 337/365 cases (279 MMRp and 58 MMRd [17,2%]). 36 of 45 tumors with MLH1 +/- PMS2 deficiency had MLH1-PM analysis, identifying MLH1-PM in 28 (77.8%) and classifying 8 (22.2%) without PM as “probable” Lynch. MMRd tumors were detected at higher stages, more often showed angioinvasion and endometrioid subtype and less abnormal p53 expression compared to MMRp. Patients with MMRd/MLH1-PM more often had endometrioid histology (89% vs 76%), showed no abnormal p53 expression (0% vs 19%) compared to “probable” Lynch. 5-year PFS was 73, 81 and 100 months (p=0.343) for MMRp, MMRd/MLH1-PM, and “probable” Lynch patients, respectively.

Conclusion Significant differences in clinical characteristics were detected between MMRd and MMRp tumors, as well as between MMRd tumors depending on MLH1-PM status. Thus, this analysis supports evidence of heterogeneity in MMRd tumors concerning prognosis.

Publication History

Article published online:
11 October 2022