Small study offers proof of concept and support for wider research.

Some scientists have suspected that the most common form of ovarian cancer may originate in the fallopian tubes, the thin fibrous tunnels that connect the ovaries to the uterus. Now, results of a study of nine women suggest that the genomic roots of many ovarian tumors may indeed arise in the fallopian tubes, potentially providing insights into the origin of ovarian cancer and suggesting new ways for prevention and intervention of this 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,” said 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.”

For the new study, described in the October 23 issue of the journal Nature Communications, scientists at the Johns Hopkins Kimmel Cancer Center and Dana Farber Cancer Institute in Boston collected tissue samples containing normal cells, ovarian cancers, metastases that had spread elsewhere, 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 came from five women who had been diagnosed with high grade serous ovarian tumors, the type of cancer that accounts for three quarters of the estimated 22,000 women diagnosed with ovarian cancers each year in the United States.

The scientists also collected samples from STIC lesions and normal cells from four women who had undergone prophylactic removal of their ovaries and fallopian tubes because of hereditary gene mutations in the ovarian and breast cancer-linked BRCA gene, or—in one case—a pelvic mass.

Because some of 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 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 relatively few cancer cells from the larger mass of adjacent normal cells.

The researchers stained the small cancers to highlight the cells containing mistakes in the p53 gene, which have long been linked to the onset of many cancer types. Then, the scientists used an infrared laser to peel off the highlighted area of cancer cells. Next, the scientists performed what is known as whole-exome genome sequencing—sequencing all known genes—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 swamped with DNA from normal cells, making it difficult to detect cancer-linked DNA errors, Papp said.

The Johns Hopkins and Dana Farber research teams then searched 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, including 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