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.