Universal Screening for Lynch Syndrome in Endometrial Cancers: Frequency of Germline Mutations and Identification of Patients with Lynch-Like Syndrome

Publication date: Available online 28 October 2017
Source:Human Pathology
Author(s): Jessica L. Dillon, Jorge L. Gonzalez, Leslie DeMars, Katarzyna J. Bloch, Laura J. Tafe
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 (MMR) genes MLH1, PMS2, MSH2, MSH6, or EPCAM. In 2015, our institution implemented universal screening of endometrial cancer hysterectomy specimens by MMR 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 63years old. 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 (one failure, one negative). One showed loss of MLH1/PMS2 and MSH6; two showed loss of MSH2/MSH6 and six had isolated loss of MSH6 only. Ten patients underwent genetic counseling and germline testing was performed in eight; LS was confirmed in five patients (2.1%). In addition, three 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.



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