Genetic studies by scientists in the U.S. suggest that the most common form of ovarian cancer actually starts in the fallopian tubes and takes about 6.5 years to progress to high-grade serous ovarian carcinoma (HGSOC). Research leader Victor Velculescu, M.D., Ph.D., a professor of oncology at the Johns Hopkins Kimmel Cancer Center, says that data from their small-scale genetic analysis study could lead to new approaches to preventing, diagnosing, and potentially treating the disease.
“Ovarian cancer treatments have not changed much in many decades, and this may be, in part, because we have been studying the wrong tissue of origin for these cancers,” he claims. “If studies in larger groups of women confirm our finding that the fallopian tubes are the site of origin of most ovarian cancer, then this could result in a major change in the way we manage this disease for patients at risk.”
The researchers report their findings in Nature Communications, in a paper entitled, “High Grade Serous Ovarian Carcinomas Originate in the Fallopian Tube.”
Ovarian cancer is the leading cause of death from gynecologic cancers, and the 10-year survival rate, at less than 30%, has not improved significantly during the last 30 years, the team notes. Ovarian cancer isn’t just one disease, however, but a highly heterogeneous group of diseases that includes different histological subtypes with specific clinical and molecular genetic features that are classified more broadly as type I and type II. HGSOC is the most frequent, type II form of ovarian cancer, which accounts for about 75% of all cases. Unfortunately, about 70% of HGSOC isn't diagnosed until it has already reached an advanced stage.
It has previously been suggested that fallopian tube cancers may be precursors of HGSOC, but there is little evolutionary evidence to support this idea, the researchers acknowledge. To try and provide new genetic insights, the Johns Hopkins Kimmel Cancer Center researchers, working with a team at the Dana Farber Cancer Institute, carried out whole-exome sequencing analyses of normal cells and ovarian cancers, metastases, and small fallopian tube cancers, including single-cell-layer p53 signatures and serous tubal intraepithelial carcinoma (STIC), from five women with HGSOC. The researchers also analyzed STIC lesions and normal cells from four additional women who had undergone prophylactic removal of ovaries and fallopian tubes because they either carried BRCA mutations or had a pelvic mass.
The results of genetic analysis showed that all nine patients had lost the same p53-harboring region of chromosome 17 in each cancer sample, including the early-stage STIC lesions. This indicated that abnormalities in p53 might be involved in the early stages of ovarian cancer development. “Our study highlights the role of p53 signatures as early lesions in this evolutionary paradigm,” the researchers write. Each of the nine patients had also lost parts of the chromosomes harboring BRCA1 and/or BRCA2, while four patients exhibited deletions in chromosome 10, which encompasses PTEN.
With their genomic data to hand, and reasoning that early cancer cells will exhibit fewer mutations than later-stage cancer cells, the team created an evolutionary tree of ovarian cancer among the five HGSOC patients. They concluded that the disease starts with genetic changes in STIC or earlier lesions in the fallopian tubes, which already contain sequence and structural changes in key driver genes. Statistical modeling indicated that while it probably takes an average of 6.5 years for ovarian cancer to develop from the early STIC lesions, once the cancer has reached the ovary it progresses to metastatic diseases within just 2 years. “This aligns with what we see in the clinic, that newly diagnosed ovarian cancer patients most often already have widespread disease,” Dr. Velculescu commented.
The authors admit that more work will be needed in much larger groups of women to validate their findings, but they suggest that identifying precursor lesions in the fallopian tubes could help earlier diagnosis of HGSOC. “Currently, the typical histopathologic evaluation of FTs [fallopian tubes] typically involves a cursory evaluation of one or two representative sections,” they write. “Our study suggests that systematic sectioning and extensive examination of total FTs should become common practice in pathology…. ”
A confirmation of the results could mean that fewer women would need to have their ovaries removed. “The window of time that exists between the development of a STIC lesion and metastatic disease highlights the importance of new screening approaches, such as liquid biopsy methods, for detection of ovarian cancer,” Velculescu concluded.