PurposeThe best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS.Patients and MethodsECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women.ResultsAnalysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years.ConclusionCombined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.

Background DNA polymerase epsilon (POLE) exonuclease domain mutations characterize a subtype of endometrial cancer (EC) with markedly increased somatic mutational burden. POLE mutant tumors were described as a molecular subtype with improved progression-free survival (PFS) by The Cancer Genome Atlas. This study investigates the frequency, spectrum, prognostic significance, and potential clinical application of POLE mutations in endometrioid EC patients. Methods PCR amplification and Sanger sequencing was used to test for POLE mutation in 544 tumors. Relationships between demographic, survival, clinicopathologic and molecular features were investigated. Statistical tests were two-sided. Results Thirty POLE mutations (5.6%) were identified. Mutations were associated with younger age (<60 years, P=.001). POLE mutations were detected in microsatellite stable (MSS) and unstable (MSI) tumors at similar frequencies (5.9 v 5.2%, respectively) and were most common in MSI tumors lacking MLH1 methylation (P<.001). There was no association with PFS (HR=0.22, P=.127). Conclusions Our discovery that mutations occur at equal frequency in MSS and MSI tumors and are most frequent in MSI tumors lacking MLH1 methylation has implications for Lynch syndrome screening and mutation testing. We show that POLE mutations are associated with somatic mutation in DNA mismatch repair genes in a subset of tumors. The absence of association between POLE mutation and PFS indicates POLE mutation status is unlikely to be a clinically useful prognostic marker. However, POLE testing in MSI ECs could serve as a marker of somatic origin of disease. As such, POLE tumor testing might be a valuable exclusionary criterion for Lynch syndrome gene testing.

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