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2022-RA-781-ESGO MLH1 promoter hypermethylation in mismatch repair deficient endometrial cancer. Defining a new subgroup?
  1. Nina Pauly1,
  2. Philipp Harter1,
  3. Florian Heitz1,2,
  4. Malak Moubarak1,
  5. Alexander Traut1,
  6. Sabrina Kaiser1 and
  7. Beyhan Ataseven1,3
  1. 1Department of Gynecology and Gynecological Oncology, Kliniken Essen Mitte, Essen, Germany
  2. 2Department for Gynecology with the Center for Oncologic Surgery Charité Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
  3. 3Department of Obstetrics and Gynecology, University Hospital LMU Munich, Munich, Germany


Introduction/Background 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).Identifying patients with MMRd has two clinical implications: first, detecting patients with high probability for Lynch syndrome and secondly classification into molecular subtypes for prognosis and/or prediction of therapy. 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.

Methodology 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). 36 of 45 tumors with MLH1 +/- PMS2 deficiency had MLH1-PM analysis, identifying MLH1-PM in 28 (77.8%). 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-PM were significantly older (65 y vs 56 y), 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.

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