Frequent loss of mutation-specific mismatch repair protein expression in nonneoplastic endometrium of Lynch syndrome patients

Lynch syndrome is most often caused by a germline mutation in one of four DNA mismatch repair (MMR) genes (MLH1, PMS2, MSH2, or MSH6) or EPCAM and is associated with a significantly increased risk of endometrial cancer in affected women. Although universal screening of endometrial cancer for Lynch syndrome is becoming increasingly common by various algorithms using MMR immunohistochemistry and/or microsatellite instability testing by PCR, establishing the diagnosis of Lynch syndrome can be still challenging. MMR-deficient nonneoplastic colonic crypts have been recently described in Lynch syndrome patients with colorectal carcinoma, and have been proposed to be a novel indicator of Lynch syndrome. Presence of MMR-deficient nonneoplastic endometrial glands have not yet been systematically evaluated in Lynch syndrome patients. We performed MMR protein immunohistochemistry in prophylactic hysterectomies and endometrial curettings/biopsies from 27 patients with known Lynch syndrome confirmed by germline mutation analysis. A total of 56 control benign endometrial tissues were also analyzed, and included benign endometrium adjacent to MMR-deficient sporadic (MLH1 promoter hypermethylated) endometrial carcinoma (n = 9), adjacent to MMR-intact sporadic endometrial carcinoma (n = 27), and normal endometrium from hysterectomies performed for benign disease (n = 20). MMR protein deficient nonneoplastic endometrial glands were identified in 70% (19 of 27) of Lynch syndrome patients. In all 19 cases the MMR protein loss was specific for the patients' known germline mutation. None of the control cases showed loss of MMR protein expression in nonneoplastic endometrium. Our findings suggest that MMR-deficient nonneoplastic endometrial glands may be a unique, specific marker of Lynch syndrome, and may provide an important insight into the pathogenesis of Lynch syndrome-associated endometrial cancer. Evaluation of MMR protein expression of benign background endometrium in endometrial cancer patients may be further explored as a possible useful addition to the Lynch syndrome screening algorithm.