Posted September 26, 2018
Robert Kurman, M.D., Tian-Li Wang, Ph.D., Kala Visvanathan, M.D., Ie-Ming Shih, M.D., Ph.D., Gary Rosner, Ph.D., Leslie Cope, Ph.D., Johns Hopkins University
Douglas Levine, M.D., Robert Soslow, M.D., Memorial Sloan-Kettering Cancer Center
Patricia Shaw, M.D., Toronto University Health Network
Vinita Parkash, M.D., Yale University

The lack of understanding surrounding the early events that occur during ovarian cancer has hindered the development of a screening approach that can reliably be used for early detection. An effective screening approach is desperately needed by the ovarian cancer community, as 85% of cases are diagnosed in the later stages after the cancer has spread. To help facilitate development of screening approaches, the Ovarian Cancer Research Program (OCRP) sought to promote a major multi-institutional research effort conducted by leading ovarian cancer researchers that specifically focused on identifying and characterizing early changes in ovarian cancer.

In fiscal year 2010, the OCRP awarded the Ovarian Cancer Consortium Award to a promising group of established ovarian cancer scientists. The consortium consisted of a coordinating center headed by Dr. Robert J. Kurman, and research directors, Drs. Tian-Li Wang and Ie-Ming Shih at the Johns Hopkins University. The research studies were performed at four academic sites: Johns Hopkins University, the Toronto University Health Network, Yale University, and Memorial Sloan-Kettering Cancer Center. Their mission was to elucidate the pathogenesis of ovarian cancer by characterizing the origin and etiology (or cause) of high-grade ovarian serous carcinoma (HGSC), the most common and most malignant form of ovarian cancer. The results obtained from the consortium have provided valuable insights into the origin and etiology of ovarian cancer and have implications for the prevention, detection, and treatment of the disease.

Recent evidence has suggested that ovarian cancer begins in the fallopian tube, rather than the ovaries. A lesion (area of abnormal tissue) in the fallopian tube, referred to as a serous tubal intraepithelial carcinoma (STIC), is identified in about 50% of HGSC. The presence of a STIC indicates fallopian tube origin, but it is unclear whether all HGSC cases have the same tubal origin. The consortium investigators sought to confirm the tubal origin of HGSC with associated STICs and identify the origin of HGSC without associated STICs. To accomplish this, the investigators used molecular profiling, which is capable of distinguishing tumors of different sites of origin. Molecular analysis of HGSC with and without associated STICs revealed molecular profiles more similar to normal fallopian tube epithelium than ovarian epithelium, indicating that they share a common origin, the fallopian tube.¹

To determine the etiology of HGSC, the consortium investigators used sequencing to identify the molecular changes in nine patients throughout ovarian cancer development�from fallopian tube lesions to ovarian cancer to metastasis. The most notable events in cancer development were the presence of STICs and changes in the sequence of TP53, a well-known tumor suppressor gene whose mutations are frequent in all cancer types. These changes were specific to the fallopian tube, as no TP53 mutations were found on the ovarian surface in early cancer development. The results suggest a progression for ovarian cancer development from normal fallopian tube epithelia to TP53 mutations, on to STIC lesions, and finally on to ovarian cancer. The consortium investigators used a mathematical model to estimate the time interval between STIC occurrence and the presence of cancer cells. The transition from STIC to ovarian cancer averaged 6.5 years, while the progression from ovarian cancer to metastasis was more rapid, averaging 2 years. These results suggest that ovarian cancer is a disease of the fallopian tubes, with the development of TP53 alterations and STICs as early events.²

In all, the consortium was highly successful, generating more than 76 original publications in research journals and at least 38 presentations at conferences, meetings, symposia, and academic centers, nationally and internationally. Publicly available data, shared reagents and information are also curated in www.ovariancancerprevention.org, the consortium website. The consortium's results confirming the fallopian tube as the site of origin for HGSC could have major implications for early detection, further propelling the research by other teams focusing on this exciting topic. These results suggest that the fallopian tubes should be targeted in screening methods with a possible focus on the early events of TP53 alterations and STIC formations.

The consortium's results could also impact ovarian cancer prevention means in high-risk women, as well as the general population. Currently, ovaries and fallopian tubes are removed to prevent ovarian cancer; this occurs both in high-risk women and older women who are undergoing a hysterectomy in order to reduce the risk of ovarian cancer. This is not ideal, as preservation of the ovaries provides long-term benefits, and their removal can contribute to an increased risk of coronary heart disease and other illnesses. The consortium's results suggest that removal of only the fallopian tubes may be sufficient to prevent ovarian cancer, thus preventing removal of the ovaries and the other associated health risks.

References/Works Cited:

(1) Ducie J, Dao F, Considine M, et al. 2017. Molecular analysis of high-grade serous ovarian carcinoma with and without associated serous tubal intra-epithelial carcinoma. Nat Commun. 8:990.

(2) Labidi-Galy SI, Papp E, Hallberg D, et al. 2017. High grade serous ovarian carcinomas originate in the fallopian tube. Nat Commun. 8:1093.

Links:

Pathogenesis of Ovarian Serous Carcinoma as the Basis for Immunologic Directed Diagnosis and Treatment

http://www.ovariancancerprevention.org/

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