Efficient screening strategy for Lynch syndrome in Japanese endometrial cancer

Lynch syndrome (LS) is an inherited disorder caused by a germline mutation in the DNA mismatch repair (MMR) genes and is associated with increased risk of various cancers, particularly colorectal cancer and endometrial cancer (EC). It is significant to identify LS in EC patients for prediction and prevention of the succeeding other associated cancers. However, useful LS screening guidelines for EC have not been established. The purpose of our study is to devise an efficient and practical screening strategy for LS in EC. We designed original criteria, named "APF criteria," with lenient terms (Age of onset < 50, or Personal or Family history of associated cancers) and applied it to unselected EC patients. We performed immunohistochemistry (IHC) and the methylation assay of MutL homolog 1 (MLH1) gene promoter using the tumors of patients who met our criteria, and thus selected "suspected LS" as the candidates for genetic analyses. Of 360 EC patients, 187 (51.9%) met the APF criteria, and the tumor specimens were available from 182 out of the 187 patients. IHC revealed that expression of at least one MMR protein was absent in cell nuclei of 54 (29.6%) tumors. Of 20 tumors lacking MLH1 protein expression, 14 cases were judged sporadic EC because of the hypermethylated MLH1 promoter. We thus selected 40 (11.1%) of 360 EC patients as "suspected LS." Our strategy that consists of clinical triage and the molecular analyses is expected to improve the screening efficiency and reduce the cost of LS identification in EC.