The endoglin–BMP9 axis as a predictor of methotrexate resistance in low-risk gestational trophoblastic neoplasia

Abstract

Objectives: Universal screening for Lynch syndrome (LS) using immunohistochemistry (IHC) is recommended for patients with new colon cancer. While the sentinel malignancy in women with Lynch syndrome is equally as likely to be endometrial cancer compared to colon cancer, universal screening in endometrial cancer has not been implemented on such a large scale. Our study aims to determine any associations between loss of MMR expression and tumor clinico-pathologic characteristics, as well as the number of germ line mutations identified using IHC at our institution. Methods: A retrospective review of patients who underwent hysterectomy for grade 1 or 2 endometrioid endometrial cancer between August 2012 and January 2014 was performed. Only patients who underwent IHC for deficiencies of MLH1, MSH2, MSH6, and PMS2 were included in this cohort. Patient charts were reviewed and patient demographics, tumor size, grade, invasion, and stainingwere abstracted from electronic medical records. Results: 180 patients underwent hysterectomy for low grade EEC during the study period. Of these, 102 (56.6%) had IHC to evaluate for MMR protein deficiencies. Twenty six (25.5%) tumors had MMR loss detected via IHC, with 19 (18.6%) having deficiencies in MLH1/ PMS2 and 3 (2.9%) in MSH2/MSH6. Loss of single protein expression was observed in 4 patients, with loss of MSH6 expression noted in 2 (2.0%) and loss of MLH1 and PMS2 in 1 (1%) each. MLH1 promoter methylation analysis was performed in 7 (35.0%) of the 20 tumors, showing methylation in 6 (85.7%). One patient with MSH2 and MSH6 loss by IHC was found to have a germline mutation in MSH6. Grade 2 tumors were significantly associated with MLH1 loss on multivariate analysis (OR 5.3, p = 0.012, 95% CI 1.4–19.8). Increasing age was associated with MLH1 and PMS2 loss (OR 1.2, p = 0.021, 95% CI 1.0– 1.3). Younger age was significantly associated with MSH6 loss (OR 0.79, p = 0.025, 95% CI .64–.97). Conclusions: The most common deficiency detected via IHC involves MLH1 and PMS2 loss and is significantly associated with age. Loss of MSH6 is significantly associated with younger age. Large studies with cost-effectiveness analyses must be performed to determine if implementation of a standardized screening regimen is necessary.