Aberrant DNA methylation is associated with the oncogenesis of a variety of human cancers, including endometrial cancer (eC), the seventh most common cancer among women. obesity is known to be a high-risk factor for EC; however, whether obesity influences DNA methylation in the presymptomatic uterus and if this influences EC development remain unclear. Here, we performed genome-wide DNA methylation analysis of isolated endometrial epithelial cells obtained from obese presymptomatic participants. Using the Illumina MethylationEPIC array (850 K), we identified 592 differentially methylated regions (DMRs), most of which undergo hypomethylated changes. these DMRs were enriched for pyrimidine metabolism, epstein-Barr virus infection, and B cell signaling pathways, indicating obesity-related dysregulation of certain metabolic processes in the presymptomatic uterus. Comparison of the DMRs with those in stage I EC revealed that 54 DMRs overlapped; additionally, B cell signaling and epstein-Barr virus infection pathways were shared between the presymptomatic uterus of obese women and stage I eC with greater hypomethylation in women with eC than in presymptomatic obese women. These findings indicated that obesity influences DNA methylation in presymptomatic endometrial epithelial cells, and persistent dysregulation of DNA methylation in obese women may result in eC development.Endometrial cancer (EC) is the seventh most common cancer among women, with 13,951 new cases and 2,243 deaths in Japan in 2014 1 . EC originates from endometrial epithelial cells, whereas endometriosis develops from endometrial stromal cells. The disease rate increases with age, peaking in the fifth-sixth decades of life. Based on differences in epidemiology and histopathology, there are two subtypes of EC: type I and type II. Type I endometrioid endometrial cancer accounts for approximately 80% of cases, occurs frequently in pre-and peri-menopausal women, is often well differentiated, and is correlated with obesity and overexposure to estrogen. Type II non-endometrioid endometrial cancer is more common in older, non-obese post-menopausal women and is poorly differentiated. Recent evidence revealed genetic alterations in the RTK/RAS/β-catenin and PI3K/ AKT/PTEN pathways in endometrial tumor tissue 2 ; however, it has also been reported that a significant subset (e.g. ~50%) 3 of EC does not contain genetic mutations in PTEN, TP53, or CTNNB1, suggesting an etiology other than common genetic mutations. One of the biological processes frequently contributing to oncogenesis is epigenetic modification: heritable changes in gene expression without mutation of the amino acid sequence. A well-known epigenetic event is DNA methylation. DNA methylation regulates gene expression and microRNA stability, contributes to the cellular phenotype, and plays important roles in various cellular processes, including development, genetic imprinting, immune response, and aging 4-6 .In DNA methylation, a methyl group (-CH 3 ) is covalently bound to the cytosine residues of C...