Abstract 4475: Association of endometrial cancer risk factors and DNA methylation in benign endometrial tissue

Abstract

Abstract Background: Increased risk for endometrial cancer is related to factors such as use of unopposed estrogen and obesity, and decreased risk is associated with oral contraceptive use and smoking. However, little is known about the molecular mechanisms by which these factors influence cancer risk. DNA methylation of promoter regions in tumor suppressor genes has been linked to endometrial cancer, suggesting DNA methylation may mediate the effects of risk factors on normal endometrium, leading to increased risk for cancer. Accordingly, we explored relationships between risk factors for endometrial cancer and DNA methylation patterns assessed in normal endometrial tissue. Materials and Methods: Formalin fixed paraffin embedded endometrial tissues from 63 women aged 28-53 (median= 43) who underwent a hysterectomy for benign indications were studied. DNA isolated from 1.0-mm cores was bisulfite treated and methylation profiles were generated using Illumina's GoldenGate array which includes 1505 CpG sites representing over 800 genes. Unsupervised hierarchical clustering analysis was used to identify groups of patients with similar methylation patterns and class comparison analysis was employed to identify differentially methylated genes based on predefined categories, representing endometrial cancer risk factors. Results: Global changes in DNA methylation, as measured by total or average methylation levels or clustering analysis were not associated with age. However, methylation levels of MT1A (p=0.0002) and CDH13 (p=0.0009) were increased and methylation levels of PKD2 (p=0.0009) were decreased among older women. Increased methylation of HS3ST2 (p=0.00006), MLF1 (p=0.0001), PLAUR (p=0.0004), MLH3 (p=0.0007), ISL1 (p=0.0007), and RASSF1 (p=0.0009) was related to women with a lifetime menstrual span of more than 30 years compared to those who reported having menstruated for less than 15 years. One gene (MMP3) was more methylated in women who had an older age at menarche (14+ years old) compared to those who had a younger age at menarche (<12 years old, p=0.0008). Furthermore, unsupervised hierarchical clustering suggested that age at menarche (p=0.05) distinguished three groups of women who had distinct methylation patterns. Conclusions: Our results suggest that DNA methylation patterns at specific loci from normal tissue are related to attained age, age at menarche and the lifetime menstrual span of women. In conjunction with methylation profiling of endometrial cancer, these data may demonstrate the importance of DNA methylation as a mechanism in the pathogenesis of endometrial cancer and lead to potential biomarkers for early detection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4475. doi:1538-7445.AM2012-4475