Abstract
Background:Lynch syndrome increases lifetime risk of endometrial cancer to 40-60%. Screening with molecular tumor testing for mismatch repair (MMR) proteins have been recommended. This study aims to evaluate the incidence of MMR deficiency and germline mutation in endometrial cancer Thai patients. Methods:Immunohistochemistry for MMR proteins, including MLH1, MSH2, MSH6 and PMS2 were tested in 166 surgical specimens. Patients who had MMR deficiencies were offered genetic counseling and a germline testing using gene-panel next generation sequencing. Results:Fifty-eight of 166 patients (34.9%) had one or more MMR deficiencies which were: MLH1 and PMS2 in 42 patients (25.3%), MSH2 and MSH6 in 11 patients (6.6%), and MSH6 in 5 patients (3.0%). Of the 40 patients (24.1%) who met the revised Bethesda guidelines, 19 patients (47.5%) had MMR deficiency. In contrast, MMR deficiency was found in 39 of the 126 patients (31.0%) who did not meet the revised Bethesda guidelines. A total of 27 patients with MMR deficiencies agreed to have germline genetic testing. Germline MMR mutations were detected in 5 patients (18.5%) including MSH6 (n=2), PMS2 (n=2), and MLH1 mutations (n=1). Incidental germline mutations in other genes were detected in 3 patients (1 BRCA1, 1 PTEN, and 1 BARD1). Among 5 Lynch syndrome patients, 2 patients (40%) did not meet the revised Bethesda guidelines. Eight patients who met the revised Bethesda Guidelines but having MMR proficiency had genetic testing, but no germline mutation was detected. Conclusion:MMR deficiencies were detected in 34.9% of the endometrial cancer patients. Germline mutations were diagnosed in 3.0% of this cohort (5/166 patients). Lynch syndrome screening with MMR immunohistochemistry should be considered in all patients regardless of personal or family history of Lynch syndrome-related cancers.
Highlights
Hereditary endometrial cancer occurs in approximately 3-5% of all endometrial cancer patients
This study aims to evaluate the incidence of mismatch repair (MMR) deficiency and germline mutation in endometrial cancer Thai patients
This syndrome is associated with germline MMR gene mutations, including MLH1, MSH2, MSH6, PMS2, or EPCAM deletions, which may associate with epigenetic silencing of MSH2 (Tamura et al, 2019)
Summary
Hereditary endometrial cancer occurs in approximately 3-5% of all endometrial cancer patients. Lynch syndrome is an autosomal dominant syndrome caused by genetic defects in one or more DNA mismatch repair (MMR) genes. This syndrome is associated with germline MMR gene mutations, including MLH1, MSH2, MSH6, PMS2, or EPCAM deletions, which may associate with epigenetic silencing of MSH2 (Tamura et al, 2019). This study aims to evaluate the incidence of MMR deficiency and germline mutation in endometrial cancer Thai patients. Patients who had MMR deficiencies were offered genetic counseling and a germline testing using gene-panel generation sequencing. Eight patients who met the revised Bethesda Guidelines but having MMR proficiency had genetic testing, but no germline mutation was detected. Lynch syndrome screening with MMR immunohistochemistry should be considered in all patients regardless of personal or family history of Lynch syndrome-related cancers
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