Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population

TLDR

Defective DNA mismatch repair endometrial cancers are understudied in Japan, and data guiding management of Lynch‑like syndrome and uncertain germline variants are lacking. The study examined 395 Japanese endometrial cancer patients (median age 59) by immunohistochemistry of MLH1, MSH2, MSH6, PMS2 on FFPE sections and assessed genetic/epigenetic alterations of mismatch repair genes. Loss of mismatch repair protein expression occurred in 17.2% of cases, and among 68 deficient tumors, 17 were candidates for genetic testing, of which 14 were confirmed Lynch syndrome (5), germline VUS (2), or Lynch‑like (7); these non‑Lynch groups were older, less often met Bethesda criteria, and had fewer Lynch‑associated tumors in relatives, suggesting surveillance may be unnecessary for them.

Abstract

Abstract Background The prevalence and molecular characteristics of defective DNA mismatch repair endometrial cancers in the Japanese population have been underexplored. Data supporting clinical management of patients with Lynch-like syndrome and germline variant of uncertain significance of mismatch repair genes are still lacking. Methods Immunohistochemistry of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary endometrial cancers in 395 women with a median age of 59 years. Genetic and/or epigenetic alterations of the mismatch repair genes were also investigated. Results Loss of expression of one or more mismatch repair proteins was observed in 68 patients (17.2%). A total of 17 out of 68 patients (25%, 4.3% of all cases) were identified as candidates for genetic testing for Lynch syndrome after excluding 51 patients with MLH1 hypermethylated cancer. Fourteen of these 17 patients subjected to genetic testing were found to have Lynch syndrome (n = 5), germline variant of uncertain significance (n = 2) or Lynch-like syndrome (n = 7). Compared with patients with Lynch syndrome, those with germline variant of uncertain significance and Lynch-like syndrome tended to demonstrate an older age at the time of endometrial cancer diagnosis (P = 0.07), less fulfillment of the revised Bethesda guidelines (P = 0.09) and lower prevalence of Lynch syndrome-associated tumors in their first-degree relatives (P = 0.01). Conclusions This study provides useful information for management in patients with DNA mismatch repair endometrial cancer. Specifically, cancer surveillance as recommended in patients with Lynch syndrome might not be necessary in patients with germline variant of uncertain significance and Lynch-like syndrome and their relatives.