A new study published in Nature Communications suggests that the genomic roots of the most common form of ovarian cancer may arise in the fallopian tubes. The findings of scientists at Johns Hopkins Kimmel Cancer Center and Dana Farber Cancer Institute in Boston offer potential insights into the origin of ovarian cancer and new avenues of prevention and intervention.
A confirmation of their work may help spare some women removal of their ovaries and the loss of hormones that leads to increased risk of heart and other diseases, according to the authors.
Ovarian cancer is typically diagnosed late in most patients and less than 30% of affected women will survive beyond 10 years.
“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,” says study leader Victor Velculescu, MD, PhD, a professor of oncology at the Johns Hopkins Kimmel Cancer Center. “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.”
Investigators collected tissue samples containing normal cells, ovarian cancers, metastases that had spread elsewhere in the body, and small cancers found in the fallopian tubes, which included single cell layers of cancer called “p53 signatures” and serous tubal intraepithelial carcinoma, or STIC lesions.
All of the samples were obtained from five women who had been diagnosed with high grade serous ovarian tumors. This type of cancer accounts for three-quarters of the estimated 22,000 women diagnosed with ovarian cancers each year in the US.
Samples were also collected from STIC lesions and normal cells from four women who had undergone prophylactic removal of their ovaries and fallopian tubes due to hereditary gene mutations in the ovarian and breast cancer-linked BRCA gene. One woman in the study underwent the procedure due to a pelvic mass.
For the study, a new way to isolate the cancer cells from the adjacent normal cells needed to be developed because the cancers were extremely small. Some lesions were only one cell-layer thick. Postdoctoral fellows Eniko Papp from Johns Hopkins and S. Intidhar Labidi-Galy from Dana Farber, together with Dr. Velculescu and co-author Ronny Drapkin, MD, PhD, formerly of the Dana Farber Cancer Institute and now at the University of Pennsylvania, developed a way to isolate the sparse cancer cells.
The researchers stained the lesions to highlight the cells containing mistakes in the p53 gene, which have long been linked to the onset of many cancer types. After that, an infrared laser was used to peel off the highlighted area of cancer cells.
The team then performed whole-exome genome sequencing on all of the samples to create a catalog of the genetic blueprint of the protein coding genes in the cells’ DNA. Without this approach, the results of genomic sequencing would have been inundated with DNA from normal cells, making it difficult to detect cancer-linked DNA errors, Papp explained.
After this process, they looked for mistakes in the DNA sequences, including areas where one DNA molecule was switched for another, and spots where large regions of DNA in a particular chromosome were altered.
The results showed that all nine patients lost identical regions of chromosome 17, where the cancer-linked p53 gene is located, in each of the cancer samples. This included the early-stage STIC lesions, suggesting that the “misprinted” or flawed p53 gene is an early step in ovarian cancer development.
All nine patients also had lost portions of chromosomes containing one or both BRCA1 and BRCA2 genes, which have long been linked to hereditary as well as sporadic breast and ovarian cancers. Four patients had deletions in chromosome 10 where another cancer-linked gene called PTEN is located.
Analysis of the results of the genomic studies allowed the team to estimate the fraction of cancer cells in which a mutation was likely to occur. They reasoned that there would likely be fewer mutations in the original cancer cells than in their successors, so they created an evolutionary tree among the ovarian cancers in the five women.
They concluded that each of the women’s cancers began with mistakes in STIC or earlier lesions located in the fallopian tubes. Additional DNA mistakes were found in cancer cells lodged in the ovary near the fallopian tube and in metastatic sites. Overall, the teams say these analyses suggest that the development of cancer in the ovaries is the result of a seeding event from the initial tumor in the fallopian tubes that already contains the key DNA changes needed for this disease.
To determine the likely time for the study patients’ cancers to form, the teams used multiple statistical models that accounted for patient age at diagnosis and the total number of mutations in each patient’s cancer. Their results indicate that ovarian cancers developed from STIC lesions within an average of 6.5 years among the patients analyzed.
However, when the patients’ cancers reached their ovaries, the progression to metastatic disease was estimated to have occurred rapidly, within two years on average.
“This aligns with what we see in the clinic,” Dr. Velculescu said. “Newly-diagnosed ovarian cancer patients most often already have widespread disease.”
Dr. Velculescu cautioned that medical practice may not change much until additional studies validate their findings. Clinical trials studying the removal of fallopian tubes instead of ovaries in women with cancer-causing, hereditary BRCA1 and BRCA2 mutations are ongoing. Dr. Velculescu also noted that the fallopian-first theory may not apply to other, less common types of ovarian cancer.
“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 early detection of ovarian cancer,” he added.
The research was funded by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Commonwealth Foundation, National Institutes of Health’s National Cancer, Institute, the Department of Defense, the Honorable Tina Brozman Foundation for Ovarian Cancer Research, the SU2C-DCS International Translational Cancer Research Dream Team Grant, the Foundation for Women’s Wellness, and the Richard W. TeLinde Gynecologic Pathology Laboratory Endowment.
For more information about this study, click here.