Introduction/Background The vast majority of mismatch repair-deficient (MMRd) endometrial carcinomas (EC) are due MLH1 promoter hypermethylation. Here, we aimed to investigate the prevalence, prognosis and underlying causes (including Lynch syndrome (LS)) of MMRd EC other than MLH1 promoter hypermethylation.
Methodology From the 409 MMRd ECs that were identified by MMR-immunohistochemistry (IHC) in the PORTEC-1,-2 and -3 trials, 97 cases did not have MLH1 promoter hypermethylation. These 97 cases were analyzed by matched tumor-normal tissue targeted next-generation sequencing (NGS) for the presence of MMR and POLE mutations (class 4/5 variants). Furthermore, microsatellite instability (MSI) testing was performed. Differences in 5-year recurrence-free survival (RFS) were analysed using the Kaplan-Meier method and log-rank test. On a subset of cases NGS is pending and results will be added for the meeting.
Results In 34 cases (35%) a germline MMR mutation (LS-associated) was identified of which 8 (24%) had a second somatic hit. Upon excluding LS-associated ECs, a somatic alteration in MMR genes was observed in 52% (n=33), including double somatic hits in 35% (n=22). In the remaining 48% of cases (n=30) no MMR mutation was found of which the majority (n=22) was confirmed MSI. Rereview of all (discrepant) MMR-IHC did not reveal misinterpretation of MMRd status. Somatic POLE mutations were identified in 7/97 cases (7%). The 5-year RFS did not differ significantly between LS-associated and non-LS-associated MMRd EC (5-year RFS 94.1% [95% CI 86.5–100%] vs 93.5% [95% CI 87.5–99.9%], respectively; p=0.72; figure 1).
Conclusion Identification of an underlying cause for unmethylated MMRd is feasible in the majority of EC cases applying matched tumor-normal tissue NGS. A significant proportion was confirmed to be LS-associated or sporadic MMRd, while only a small subset remained unresolved. Although this distinction did not carry prognostic relevance, identification of definitive sporadic causes may release patients and relatives from burdensome LS-surveillance.
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