Testing for Lynch Syndrome in Endometrial Carcinoma: From Universal to Age-Selective MLH1 Methylation Analysis

Abstract

International guidelines recommend universal screening of endometrial carcinoma (EC) patients for Lynch syndrome (LS). This screening is generally based on mismatch repair (MMR) protein immunohistochemistry followed by MLH1 methylation analysis of MLH1-negative cases to exclude the likely sporadic cases from germline testing. As LS-associated EC is uncommon in the elderly, age-selective methylation testing could improve cost-efficiency. We performed MMR immunohistochemistry on 821 unselected ECs (clinic-based cohort) followed by a MLH1 promoter methylation test of all MLH1/PMS2-negative tumors. Non-methylated MLH1-deficient cases underwent NGS and MLPA-based germline analyses to identify MLH1 mutation carriers. A reduction in the test burden and corresponding false negative rates for LS screening were investigated for various age cut-offs. In addition, the age distribution of 132 MLH1 mutation carriers diagnosed with EC (registry-based cohort) was examined. A germline MLH1 mutation was found in 2/14 patients with non-methylated MLH1-deficient EC. When compared to a universal methylation analysis, selective testing with a cut-off age of 65 years, would have reduced the testing effort by 70.7% with a false negative rate for LS detection of 0% and 3% in the clinic and registry-based cohorts, respectively. The use of age-selective methylation analysis is a feasible way of reducing the costs and laboratory burden in LS screening for EC patients.

Correlation between immunohistochemical staining and clinicopathological findings in endometrial carcinoma

“…Mismatch repair deficiency has been linked to MSI, which is a hallmark of Lynch syndrome, a hereditary cancer syndrome that predisposes individuals to various malignancies, including endometrial carcinoma. 14 However, in sporadic endometrial carcinoma, MMR deficiency can occur through somatic mutations or epigenetic silencing of MMR genes. 15 The detection of MMR deficiency by immunohistochemical staining has important implications for the diagnosis, classification, and management of endometrial carcinoma.…”

Microsatellite Instability: From the Implementation of the Detection to a Prognostic and Predictive Role in Cancers

“…Although some studies showed that some MSI EC cases also harbouring other mutations overlapped with different molecular phenotypes, the TCGA classified MSI EC as a distinct molecular phenotype [ 124 ]. LS in the EC was observed with a frequency of 3% [ 125 ].…”

Immunohistochemical Markers in Endometrial Cancer: Latest Updates

“…Assuming that women with both endometrial cancer and LS are typically younger than women with endometrial cancer but without LS, Pasanen et al [4] tested whether limiting MLH1 methylation analysis to women below a certain age threshold could improve the cost-benefit ratio compared to the proposed age-independent universal screening. They tested tumor tissue samples from 842 women who underwent surgery at the Helsinki University Hospital over 5 years and from 142 women who were included in the Finnish national registry of LS patients.…”

“…If the MLH1 methylation analysis had been limited to women under 65 years, this would have excluded almost 71% of women from the analysis. If the MLH1 methylation analysis had been limited to women under 70 years, this would have excluded just over 56% of women from the analysis [4]. Considering an age threshold of 60 years, the sensitivity of the method would have been 50% for the hospitalbased cohort and 88.6% for the registry-based cohort.…”

“…A sensitivity equivalent to the latter would be obtained by considering a threshold age of 70 years. The authors concluded that in the Finnish population, limiting MLH1 methylation analysis to women older than 65 years could significantly reduce laboratory efforts while maintaining acceptable sensitivity [4].…”