DNA Methylation Patterns Between Serous Uterine and Ovarian Carcinomas Indicate Shared Markers with Fallopian Tube Epithelium and Distinctions Consistent with Histopathology

Background/Objectives: Uterine serous carcinoma (USC) is a deadly form of Type II endometrial cancer of rising incidence in the USA. It is currently thought to originate in the uterus, but emerging evidence suggests USC etiology is more complex and may involve the fallopian tube. DNA methylation is an inheritable suppressive epigenetic marker that can differentiate cellular origins, so we opted to perform a study comparing DNA methylation of USC to the fallopian tube and uterus. Methods: DNA methylation profiles were compared between USC, fallopian tube epithelium (FTE), normal uterus, and a cancer known to primarily originate from FTE: high-grade serous ovarian cancer (HGSC). Hierarchical clustering of DNA methylation was performed. Variably DNA-methylated genes were defined for tumors and the FTE relative to normal uterus. Results: Hierarchical clustering of USC separated USC from normal uterus but showed similarity with some FTE profiles, such as HGSC. Differentially methylated genes in USC correspond to both known and novel genes related to USC biology. Known biomarkers included hypomethylation of PAX8 in both HGSC and USC, which is often used in histopathology. Another known histopathological marker is WT1, which is more often expressed in HGSC than USC. By DNA methylation, hypomethylation was observed with WT1 in HGSC, whereas in USC WT1 hypermethylation was observed. Other novel markers of interest are discussed within. Conclusions: There is substantial overlap in DNA methylation biomarkers between the fallopian tube epithelium and USC tumors, just like the known FTE-originating carcinoma: HGSC. These results are supportive of the possibility of certain USCs arising first from the FTE (thereby retaining inheritable DNA methylation markers from the FTE) and then metastasizing to the uterus.