Early Precursor Escape and High-Grade Serous Carcinogenesis
Abstract
Rationale: The purpose of this study is gain understanding necessary to prevent the most dangerous ovarian cancer (serous cancer) by identifying and characterizing a newly discovered and important early pathway to this disease. Because many serous cancers originate in the fallopian tubes, obstetrician gynecologists are attempting to prevent the disease by removing the fallopian tubes at the first opportunity once a woman has concluded her childbearing. This strategy presupposes that many if not all serous cancers originate in the tube. Evidence for this is primarily the discovery of early cancers in the tube, from which it is presumed the disease spreads to the other organs. The problem: However, there are critical gaps in our understanding of just how large a role the fallopian tube plays in the development of serous cancer. The most compelling is the fact that a high percentage of women who come in with metastatic serous cancer do not have a visible "start point" in the tube. This observation — reported repeatedly from study to study — has created uncertainty over where many of these tumors start. Do they start in the ovaries, tubes, or somewhere else? The answer to this question is profoundly important to strategies for early detection or prevention. What the proposed research will do to address the problem: We recently performed a detailed analysis of "normal" fallopian tubes of a small number of women (32) with serous cancer. In this analysis, evidence of very early abnormalities (early serous proliferations) in the lining of the fallopian tubes was uncovered. These abnormal cells did not appear malignant, but contained evidence of genetic changes (mutations in the p53 gene) that are also found in serous cancer. When we analyzed the p53 mutations in the proliferations, we found that they were identical to the p53 mutations in the coexisting serous cancers. This further suggests that many metastatic serous cancers ultimately arise, not from cancers in the fallopian tube, but from benign-appearing but genetically altered cells that were shed from the serous proliferations in the tube and later underwent malignant transformation in the peritoneal cavity. This is a completely novel concept. We all know that a precancerous change in the uterine cervix might progress to invasive cancer, a process that is easily interrupted by Pap smear screening and removal of precancers. It is possible that serous cancers can arise in a similar fashion, but in this case the precancer starts in the tube and then becomes cancer in a different place (the peritoneal cavity). The proposed research will use sophisticated genetic analysis to determine (1) whether widespread serous cancers are directly related to these seemingly benign precancers in the fallopian tube and (2) whether the mechanism of cancer development begins with detachment of these cells into the peritoneal fluid. The goal of this project is to add new information that will rewrite the early phases of the life history of serous cancer. Relevance to the mission of the OCRP: The goals of this study apply to women of all ages, not only older women who are at higher risk for serous cancer, but also younger women who wish to reduce their chances of a later malignancy. The hypothesis of "precursor escape" ultimately could inform decision-making regarding the beneficial (or potentially hazardous) effects of risk-reducing salpingectomy in all women and the safety of salpingectomy with sparing of the ovaries in young women with germ-line BRCA1 or BRCA2 mutations. Moreover, as the early life history of serous cancer becomes clearer, it will likely prompt other strategies for preventing, interrupting, or intercepting serous cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910127
Entities
People
- Christopher P Crum
Organizations
- United States Army