Molecular and clinicopathologic characterization of mismatch repair-deficient endometrial carcinoma not related to MLH1 promoter hypermethylation

Kaya, M.; Post, C.C.B.; Tops, C.M.; Nielsen, M.; Crosbie, E.J.; Leary, A.; ... ; Bosse, T. (2024)

Article / Letter to editor

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 ¼ 1254), 84 MMRd EC not related to MLH1-PHM were identified that successfully underwent paired tumorenormal tissue nextgeneration sequencing 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 DSMMRd 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 POLEEDM 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 tumorenormal next-generation sequencing to identify definitive sporadic causes in MMRd EC unrelated to MLH1-PHM. MMR immunohistochemistry and POLE-EDM mutation status can aid in the differentiation between LS-MMRd EC and DS-MMRd EC.

• endometrial carcinoma
• Lynch syndrome
• PORTEC trials
• mismatchrepair-deficiency
• hereditary cancer syndromes

• All authors: Kaya, M.; Post, C.C.B.; Tops, C.M.; Nielsen, M.; Crosbie, E.J.; Leary, A.; Mileshkin, L.R.; Han, K.T.Y.; Bessette, P.; Boer, S.M. de; Jürgenliemk-Schulz, I.M.; Lutgens, L.; Jobsen, J.J.; Haverkort, M.A.D.; Nout, R.A.; Kroep, J.; Creutzberg, C.L.; Smit, V.T.H.B.M.; Horeweg, N.; Wezel, T. van; Bosse, T.
• Date: 2024-03-31
• Journal: Modern Pathology
• Volume: 37
• Issue: 3
• DOI: doi:10.1016/j.modpat.2024.100423