High-grade serous ovarian carcinoma (HGSOC) accounts for 70% of ovarian cancers and is responsible for most of the 14,000 ovarian cancer deaths in the United States each year. Because the tumor is usually widespread by the time of diagnosis, patients with HGSOC face a poor prognosis.
Recent evidence shows that this high-stage disease may result from spread of pre-cancerous cells from the fallopian tube to the abdominal lining, even before an invasive cancer has developed in the ovary or fallopian tube. This realization has led to so-called “risk reduction” surgeries, where the fallopian tubes are removed from healthy patients in order to reduce their risk of later developing HGSOC. This approach is particularly common in women with an inherited high risk of HGSOC.
Although the spread of pre-cancerous cells is thought to occur most often from the fallopian tube, there is also evidence that these pre-cancerous cells may originate in the endometrium (the lining of the uterus) in some patients. For instance, studies have shown the surgical removal of the uterus reduces the risk of HGSOC. We also know that early cancer-causing mutations can occur in the endometrium, just as they do in the fallopian tube. Finally, we know that cells can travel from the endometrium to the abdominal cavity via the fallopian tube – this is what is thought to lead to endometriosis, for example. All of these observations suggest that pre-cancerous cells may also travel from the endometrium to the abdominal cavity, where they may then develop into HGSOC.
To study this hypothesis, we will dissect normal tissue, pre-cancerous cells, and invasive cancer cells from the endometrium, the fallopian tube, and the abdominal lining. We will then perform genetic sequencing on each of these tissues separately. Shared mutations between the different tissues would indicate that these pre-cancerous and cancerous cells at different sites are genetically related. Furthermore, by analyzing the number and kind of mutations at different sites, we can create an “evolutionary tree” for HGSOC, showing where each cancer originated and how it spread. These evolutionary trees should indicate whether some HGSOC do, in fact, start in the endometrium.
This project has the potential to fill gaps in our knowledge regarding the role of the fallopian tube and the endometrium in the development of ovarian cancer. Such an advance will profoundly influence our understanding of cancer development, with serious implications for cancer prevention.
This grant was made possible in part by generous donations from OCRA Community Partners, including the Janice Lopez Ovarian Cancer Foundation, Teal There’s A Cure, Tell Every Amazing Lady About Ovarian Cancer and Toasting to Teal.
David Byron Chapel grew up on a family farm in Parma Township, Michigan. He completed undergraduate studies in microbiology and Germanic languages & literature at the University of Michigan in Ann Arbor. He began his research work during his undergraduate years, studying mechanisms of norovirus infection and propagation.
David attended medical school at the Columbia University College of Physicians and Surgeons, where he was a trainee in the Columbia-Bassett Program. While in medical school, David was a research fellow at the New York Center for Agricultural Medicine and Health, where he conducted field research in agricultural epidemiology and occupational health.
After finishing medical school, David relocated to the University of Chicago for residency training in anatomic and clinical pathology. He was a trainee in the department for four years and served one year as chief resident. During residency, David began translational clinical research in mesothelioma and in gynecologic cancer. His published studies in mesothelioma include examinations of MTAP, 5-hydroxymethylcytosine, and PD-L1 as diagnostic and predictive markers, and he is an active member of the International Mesothelioma Panel. David's published research in gynecologic oncology includes studies of PAX8 expression in peritoneal mesotheliomas, Lynch syndrome screening, and accumulation of unstable microsatellite loci in the progression from endometrial intraepithelial neoplasia to endometrioid adenocarcinoma. The latter study won the Chicago Pathology Society Resident Research Competition and received a Stowell-Orbison Certificate of Merit at the 108th annual meeting of the United States and Canadian Academy of Pathology.
David is currently a fellow in Women's and Perinatal Pathology at the Brigham and Women's Hospital, where he remains actively involved in clinical and research work, with ongoing projects examining the molecular determinants of patient outcome in mucinous ovarian tumors. David occupies his spare time comparing recordings of orchestral music and opera, cooking and baking, and meeting friends for brunch.