Biologic rationale of fallopian tube removal to prevent uterine serous carcinoma - ABSTRACT Uterine cancer incidence is rising. Much of this increase is due to a deadly form of endometrial, or uterine, cancer: uterine serous carcinomas (USC). Endometrial carcinoma is often segregated into two subtypes: type I and type II. Type I is common, less aggressive, estrogen linked, and has better prognosis. Type II tumors, which are >90% USC, make up 10% of the uterine cancer population, yet are responsible for 40% of the deaths. Almost all type II tumors are p53-mutant USCs. While characterizing our new spontaneous mouse model intended to create fallopian cancer, we serendipitously discovered that USC can originate from the fallopian tube. An observational study in humans found that fallopian tubal ligation may reduce the rate of type II endometrial cancers by 75%, but the reasons why were speculative. To better understand the human observational study, we propose mouse experimentation and human bioinformatic comparisons. In mice, we will utilize a spontaneous mouse model of fallopian cancer development, the Trp53em1Jdel_Tg(Ovgp1-Trp53*R270H-Myc). Characterization of the model has shown cancerous cells start on the fallopian tube epithelium and are later found in the uterine epithelium. Aim 1 will test murine surgical methods of removing the ovary and fallopian tube, which we predict to reduce the rates of cancer cell identification within the uterus. Aim 2 will utilize lentiviral cell barcoding at the murine fallopian tube to determine how cells move from the fallopian tube to the uterus and then metastasize throughout the abdominal cavity. Aim 3 will characterize DNA methylation patterns of human USC and compare to normal tissue patterns within the fallopian tube and uterus to define what fraction of USC clusters with which possible origin site. Taken together, this study will establish rationale of how and why prevention of human USC may be made through preventative surgeries.
