Universal screening for Lynch syndrome in endometrial cancers: frequency of germline mutations and identification of patients with Lynch-like syndrome

• Published in: Human pathology 2017-12, Vol.70, p.121-128
• Main Authors: Dillon, Jessica L., Gonzalez, Jorge L., DeMars, Leslie, Bloch, Katarzyna J., Tafe, Laura J.
• Format: Article
• Language: English
• Subjects: Adult; Age; Aged; Aged, 80 and over; Biomarkers, Tumor - genetics; Cloning; Colorectal cancer; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - pathology; Deoxyribonucleic acid; DNA; DNA Methylation; DNA Mutational Analysis; DNA-Binding Proteins - genetics; Early Detection of Cancer - methods; Endometrial cancer; Endometrial carcinoma; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Endometrial Neoplasms - surgery; Epithelial Cell Adhesion Molecule - genetics; Family medical history; Female; Gastroenterology; Genetic Counseling; Genetic disorders; Genetic Predisposition to Disease; Genetic testing; Germ-Line Mutation; Germline; Gynecology; Heredity; Humans; Hysterectomy; Immunohistochemistry; Laboratories; Lynch syndrome; Lynch-like syndrome; Middle Aged; Mismatch repair; Mismatch Repair Endonuclease PMS2 - genetics; Mutation; Mutation Rate; MutL Protein Homolog 1 - genetics; MutS Homolog 2 Protein - genetics; Patients; Pedigree; Phenotype; Predictive Value of Tests; Protein expression; Proteins; Retrospective Studies; Studies; Tumors
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2017.10.022

Lynch syndrome (LS) is an inherited clinical syndrome characterized by a high risk of colorectal, endometrial (lifetime risk of up to 60%), ovarian, and urinary tract cancers. The diagnosis is confirmed by identification of germline mutations in the DNA mismatch repair genes MLH1, PMS2, MSH2, MSH6, or EPCAM. In 2015, our institution implemented universal screening of endometrial cancer (EC) hysterectomy specimens by mismatch repair immunohistochemistry (IHC) with reflex MLH1 promoter hypermethylation analysis for tumors with loss of MLH1/PMS2 expression. Patients with tumors negative for MLH1 methylation and those with a loss of the heterodimer pair MSH2 and MSH6, or isolated loss of either PMS2 or MSH6 were referred to the Familial Cancer Program for genetic counseling and consideration of germline testing. Between May 2015 to Dec 2016, 233 EC patients were screened by IHC for LS with a median age of 63 years. Sixty tumors (27%) had abnormal IHC staining results. Fifty-one (22%) harbored heterodimeric loss of MLH1 and PMS2, 49 of which showed MLH1 promoter methylation (1 failure, 1 negative). One showed loss of MLH1/PMS2 and MSH6, 2 showed loss of MSH2/MSH6, and 6 had isolated loss of MSH6 only. Ten patients underwent genetic counseling, and germline testing was performed in 8; LS was confirmed in 5 patients (2.1%). In addition, 3 patients with negative germline testing and presumed Lynch-like syndrome were identified and offered additional somatic testing. Universal screening for LS in EC patients has yielded positive results for identification of patients at risk for this inherited syndrome. •LS universal screening identified 27% of EC cases with abnormal IHC staining results.•MLH1 promoter methylation was positive in a majority with heterodimeric loss of MLH1 and PMS2.•Ten patients were referred for genetic counseling, and germline testing was performed in 8.•LS was confirmed in 5 patients (2.1%).•Three patients with negative germline testing result and presumed Lynch-like syndrome were identified.