Molecular and Clinicopathologic Characterization of Mismatch Repair-Deficient Endometrial Carcinoma Not Related to MLH1 Promoter Hypermethylation

Merve Kaya, Cathalijne C B Post, Carli M Tops, Maartje Nielsen, Emma J Crosbie, Alexandra Leary, Linda R Mileshkin, Kathy Han, Paul Bessette, Stephanie M de Boer, Ina M Jürgenliemk-Schulz, Ludy Lutgens, Jan J Jobsen, Marie A D Haverkort, Remi A Nout, Judith Kroep, Carien L Creutzberg, Vincent T H B M Smit, Nanda Horeweg, Tom van WezelTjalling Bosse*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch repair-deficient (MMRd) EC without MLH1 promoter hypermethylation (PHM). LS is confirmed through the identification of germline MMR pathogenic variants (PV). In cases where these are not detected, emerging evidence highlights the significance of double somatic MMR gene alterations as a sporadic cause of MMRd, alongside POLE/POLD1 exonuclease domain (EDM) PV leading to secondary MMR PV. Our understanding of the incidence of different MMRd EC origins not related to MLH1-PHM, their associations with clinicopathologic characteristics, and the prognostic implications remains limited. In a combined analysis of the PORTEC-1, -2, and -3 trials (n=1254), 84 MMRd EC not related to MLH1-PHM were identified and underwent paired tumor-normal tissue next-generation sequencing (NGS) of the MMR and POLE/POLD1 genes. Among these, 37% were LS-associated (LS-MMRd EC), 38% were due to double somatic hits (DS-MMRd EC), and 25% remained unexplained. LS-MMRd EC exhibited higher rates of MSH6 (52% vs. 19%) or PMS2 loss (29% vs. 3%) than DS-MMRd EC, and exclusively showed MMR-deficient gland foci. DS-MMRd EC had higher rates of combined MSH2/MSH6 loss (47% vs. 16%), loss of >2 MMR proteins (16% vs. 3%), and somatic POLE-EDM PV (25% vs. 3%) than LS-MMRd EC. Clinicopathologic characteristics, including age at tumor onset and prognosis, did not differ among the various groups. Our study validates the use of paired tumor-normal NGS to identify definitive sporadic causes in MMRd EC unrelated to MLH1-PHM. MMR-IHC and POLE-EDM mutation status can aid in the differentiation between LS-MMRd EC and DS-MMRd EC. These findings emphasize the need for integrating tumor sequencing into LS diagnostics, along with clear interpretation guidelines, to improve clinical management. While not impacting prognosis, confirmation of DS-MMRd EC may release patients and relatives from burdensome LS-surveillance.
Original languageEnglish
Article number100423
Number of pages13
JournalModern Pathology
Volume37
Issue number3
DOIs
Publication statusPublished - Mar 2024

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