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Targeted Next-Generation Sequencing of MLH1, MSH2, and MSH6 Genes in Patients with Endometrial Carcinoma under 50 Years of Age

ABSTRACT: Background:Lynch syndrome is an inherited cancer disorder that causes an increased lifetime risk of various types of cancers. Endometrial cancer is the most common extracolonic cancer in Lynch syndrome. Guidelines recommend that patients with endometrial cancer younger than 50 years of age should be evaluated for Lynch syndrome. Molecular analysis of the mismatch repair genes and EPCAM gene is required for a definitive diagnosis of Lynch syndrome. Aims:To report the mutation analysis of mismatch repair genes using targeted next-generation sequencing in endometrial cancer diagnosed patients <50 years of age. Study Design:Retrospective cross-sectional study. Methods:Seventy-nine endometrial cancer diagnosed patients <50 years of age underwent genetic counseling. They were selected among 1094 consecutive endometrial cancer patients between 2006 and 2017. Molecular analysis of MLH1, MSH2, and MSH6 genes was performed in 79 patients by using next-generation sequencing. Deletion/duplication analysis of mismatch repair genes and EPCAM gene was also performed in 79 patients by using the multiplex ligation-dependent probe amplification method. Results:Germline testing of mismatch repair genes was performed in 79 endometrial cancer patients. Lynch syndrome was confirmed in 4 patients (5%; 4/79). A total of 14 variants (6 in MSH2, 5 in MLH1, 3 in MSH6 genes) were found in 14 patients. Four variants were assessed as pathogenic/likely pathogenic, and 10 variants were assessed as variants of uncertain significance. Conclusion:Lynch syndrome should be investigated in patients diagnosed with endometrial cancer that are less than 50 years of age due to the increased lifetime risk of developing cancer.

SUBMITTER: Ozdemir TR

PROVIDER: S-EPMC6335935 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Targeted Next-Generation Sequencing of <i>MLH1, MSH2</i>, and <i>MSH6</i> Genes in Patients with Endometrial Carcinoma under 50 Years of Age

Özdemir Taha Reşid TR Alan Murat M Sancı Muzaffer M Koç Altuğ A

Balkan medical journal 20180921 1

<h4>Background</h4>Lynch syndrome is an inherited cancer disorder that causes an increased lifetime risk of various types of cancers. Endometrial cancer is the most common extracolonic cancer in Lynch syndrome. Guidelines recommend that patients with endometrial cancer younger than 50 years of age should be evaluated for Lynch syndrome. Molecular analysis of the mismatch repair genes and <i>EPCAM</i> gene is required for a definitive diagnosis of Lynch syndrome.<h4>Aims</h4>To report the mutatio ...[more]

PMID: 30238922

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Project description:ObjectiveUniversal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to determine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1-methylated tumors.MethodsWe screened blood for constitutional MLH1 methylation using pyrosequencing and real-time methylation-specific PCR in patients with MMRd, MLH1-methylated EC ascertained from (i) cancer clinics (n = 4, <60 years), and (ii) two population-based cohorts; "Columbus-area" (n = 68, all ages) and "Ohio Colorectal Cancer Prevention Initiative (OCCPI)" (n = 24, <60 years).ResultsConstitutional MLH1 methylation was identified in three out of four patients diagnosed between 36 and 59 years from cancer clinics. Two had mono-/hemiallelic epimutation (∼50% alleles methylated). One with multiple primaries had low-level mosaicism in normal tissues and somatic "second-hits" affecting the unmethylated allele in all tumors, demonstrating causation. In the population-based cohorts, all 68 cases from the Columbus-area cohort were negative and low-level mosaic constitutional MLH1 methylation was identified in one patient aged 36 years out of 24 from the OCCPI cohort, representing one of six (∼17%) patients <50 years and one of 45 patients (∼2%) <60 years in the combined cohorts. EC was the first/dual-first cancer in three patients with underlying constitutional MLH1 methylation.ConclusionsA correct diagnosis at first presentation of cancer is important as it will significantly alter clinical management. Screening for constitutional MLH1 methylation is warranted in patients with early-onset EC or synchronous/metachronous tumors (any age) displaying MLH1 methylation.

Dataset Information

Targeted Next-Generation Sequencing of MLH1, MSH2, and MSH6 Genes in Patients with Endometrial Carcinoma under 50 Years of Age

Publications

Targeted Next-Generation Sequencing of <i>MLH1, MSH2</i>, and <i>MSH6</i> Genes in Patients with Endometrial Carcinoma under 50 Years of Age

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