| Background. Endometrial adenocarcinoma (EC) is the most common gynecological cancer and the fourth most common cancer in Canadian and Albertan women. Changes in genome-wide (i.e., global) DNA methylation is an important epigenetic process integral in cancer development. The primary goal of this study was to compare global DNA methylation in endometrioid and serous endometrial adenocarcinomas relative to normal (atrophic) endometrial tissue. Additionally, we explored associations between selected EC risk factors (e.g., estrogen and progesterone hormone replacement therapy [E+P HRT] and oral contractive [OC] use) and dietary and lifestyle influences (e.g., dietary folate) and subgroups of EC defined by methylation levels. Methods. DNA for methylation analysis was obtained from paraffin-embedded tumor tissue from cases in a population-based case-control study in Alberta and paraffin-embedded atrophic endometrial tissue from hysterectomies performed at the Foothills Medical Centre Calgary, Alberta. Global DNA methylation levels were calculated using reverse-phase high-performance liquid chromatography (rp-HPLC) and a student's t-test was used to compare mean percent methylation across histology and grade. Risk factors for subgroups of EC defined by methylation levels were explored with polytomous logistic regression using cases and controls from the Alberta case-control study. Results. Endometrioid (3.7%, 95% confidence interval (CI): 3.6-3.8) and serous (3.7%, 95% CI: 3.5-3.9) EC were significantly hypermethylated relative to normal tissue (3.4%, 95% CI: 3.3-3.6) [p=0.006 and p=0.01, respectively]. Among endometrioid tumors, high grade endometrioid tumors were significantly hypomethylated relative to low grade endometrioid tumors [p=0.005]. Women who used OCs (versus never users) had a particularly strong reduction in risk for EC defined by low global DNA methylation (0.28, 95% CI: 0.09-0.8). Current smokers and women who breastfed had an elevated (4.68, 95% CI: 1.27-17.21) and reduced risk (0.26, 95% CI: 0.07-1.0), respectively, for EC with high global DNA methylation. Discussion. These results suggest that DNA methylation either has a role in, or is a marker for, EC tumorigenesis and this is the first study to suggest that DNA methylation can be influenced by EC risk factors. |
