Context-dependent environmental associations with endometrial cancer histotype and genotype.

OBJECTIVE: MLH1 loss due to MLH1 methylation, detected during Lynch syndrome screening, is one of the most common molecular changes in endometrial cancer. It is well established that environmental influences such as nutritional state can impact gene methylation, both in the germline and in a tumor. In colorectal cancer and other cancer types, aging is associated with changes in gene methylation. The objective of this study was to determine if there was an association between aging or body mass index on MLH1 methylation in sporadic endometrial cancer. METHODS: A retrospective review of patients with endometrial cancer was performed. Tumors were screened for Lynch syndrome via immunohistochemistry, with MLH1 methylation analysis performed when there was loss of MLH1 expression. Clinical information was abstracted from the medical record. RESULTS: There were 114 patients with mismatch repair deficient tumors associated with MLH1 methylation, and 349 with mismatch repair proficient tumors. Patients with mismatch repair deficient tumors were older than those whose tumors were proficient. Mismatch repair deficient tumors had a higher incidence of lymphatic/vascular space invasion. When stratified by endometrioid grade, associations with body mass index and age became apparent. Patients with endometrioid grades 1 and 2 tumors and somatic mismatch repair deficiency were significantly older, but body mass index was comparable with that of the mismatch repair intact group. For endometrioid grade 3, patient age did not significantly vary between the somatic mismatch repair deficient group and the mismatch repair intact group. In contrast, body mass index was significantly higher in the patients with grade 3 tumors with somatic mismatch repair deficiency. CONCLUSION: The relationship of MLH1 methylated endometrial cancer with age and body mass index is complex and somewhat dependent on tumor grade. As body mass index is modifiable, it is possible that weight loss induces a 'molecular switch' to alter the histologic characteristics of an endometrial cancer.