Evaluation of DNA Mismatch Repair Protein Expression as a Preliminary Screening for Lynch Syndrome in Young Japanese Women with Endometrial Cancer

Abstract

Background: Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant cancer syndrome. There is an urgent need to identify patients with Lynch syndrome among patients with endometrial cancer. We aimed to evaluate the efficacy of measuring DNA mismatch repair (MMR) expression in young Japanese endometrial cancer patients to differentiate sporadic and Lynch syndrome-associated tumors. Methods: In a retrospective analysis of 50-year-old or younger endometrial cancer patients, 106 tumors were evaluated for MSH2, MSH6, PMS2, and MLH1 expression by immunohistochemistry. Samples lacking MLH1 were further examined by real-time PCR to evaluate hypermethylation of the MLH1 promoter. Clinical characteristics of patients with suspected Lynch syndrome were then evaluated. Results: Among the 106 samples, 25 (23.6%) had reduced MMR protein expression; MLH1, MSH2 and MSH6 staining was negative in 14, 6 and 5 cases, respectively, while no samples were negative for PMS2. Among the 14 cases lacking MLH1 staining, 10 were found to be associated with MLH1 promoter hypermethylation. Therefore, 15 (14.2%) cases of suspected Lynch syndrome-associated endometrial cancer were found. These patients presented with a significantly lower body mass index and had more first-degree relatives diagnosed with a Lynch syndromeassociated cancer. Our cohort included three Lynch syndrome patients with known mutations, and tumor samples from these patients showed an absence of the specific MMR protein that was mutated. Conclusions: Our results demonstrate that immunohistochemical analysis of tumor samples for MMR protein expression can identify patients with Lynch syndrome. With early detection, colorectal cancer outcomes might be drastically improved.