Portland, Ore.

Lack of a certain protein that repairs chromosomes seems to be the culprit for increased ovarian cancer risk

A research team from the Oregon Health & Science University Cancer Institute has made a significant breakthrough in identifying women who are likely to get breast and ovarian cancer.

Some women do not have mutations in either of the two genes for breast and ovarian cancer  - BRCA1 and BRCA2 - but still have a strong family history of ovarian and breast cancer. Researchers have wondered whether the cause is genetic.

"We knew that there must have been something else that we could track genetically," said the study's principal investigator Tanja Pejovic, M.D., Ph.D., associate professor of obstetrics and gynecology, OHSU School of Medicine, and one of the founding members of the Center for Reproductive Malignancies of the OHSU Cancer Institute.

The research, "Cytogenetic Instability in Ovarian Epithelial Cells From Women at Risk of Ovarian Cancer," will be published Friday, Sept. 15, in the journal Cancer Research.  

What the research team found was that women who have a family history of ovarian cancer but do not have the BRCA mutations, have a low level of the Fanconi anemia protein known as FANCD2. Normally this protein protects DNA and helps repair broken chromosomes so cells from the ovary in at-risk women were unable to be repaired. Therefore, well before cancers developed, the cells from the ovary were at high risk of developing cancer causing mutations. Cells from other parts of the body were normal.

"Basically we have discovered that by testing ovarian cells for chromosome breakage, we may be able to identify many more women at risk for ovarian and breast cancer than by using BRCA1 and BRCA2 mutation testing. We are also suggesting that that low levels of FANCD2 protein are associated with this increased chromosome breakage," said Pejovic.

Pejovic believes that the method might lead to the development of a screening method using minimally invasive surgery to remove a few epithelial cells from the ovary. The cells can be tested for chromosomal breakage.

"Once this method is fully developed, we will be able to tell a young woman who has a family history of ovarian or breast cancer, but who wants to have children, whether she is at risk or not, without removing her ovary."

For the study, however, ovarian samples were collected intraoperatively after having obtained signed informed consent from women undergoing primary surgery for benign gynecologic disease, ovarian cancer patients undergoing an initial procedure, and from women at high risk for ovarian cancer undergoing a preventive removal of their ovaries. Patients at high risk for ovarian cancer were defined as women with a family history of one or more first-degree relatives (mother, grandmother) diagnosed with ovarian cancer prior to the age of 50, a family history of one first-degree relative with ovarian cancer and one or more first-or second-degree relatives (aunts, sisters) diagnosed with breast or ovarian cancer, or a personal history of breast cancer and one or more first- or second-degree relatives diagnosed with breast or ovarian cancer. None of the patients had received any chemotherapy or radiation prior to surgery.

Researchers screened ovarian surface epithelial cells from 25 primary cultures established from 22 patients. Samples were obtained from women at high risk for ovarian cancer with normal ovaries; ovarian cancer patients; and a control group with no family history of breast or ovarian cancer.

Other members of the team include Grover Bagby, M.D., director of the OHSU Cancer Institute and Pejovic's research mentor, and Laura Hays, M.D., a postdoctoral fellow in Bagby's laboratory. Pejovic said that the next step is to apply her findings in a large multi institute study looking at the genetic composition of the female participants.

Ovarian cancer is the deadliest gynecological cancer and the fourth leading cause of death among women in the United States. Ovarian cancer, is very treatable if detected early, but in the vast majority of cases ,the cancer is not diagnosed until it has spread beyond the ovaries. Many women do not recognize the symptoms of ovarian cancer, which include abdominal bloating or discomfort, nausea, indigestion, gas, constipation, diarrhea or frequent urination, unusual fatigue, unexplained weight loss or shortness of breath.

Pejovic's expertise is in cancer genetics and her clinical experience is in women's cancers. She is searching for new therapies for ovarian cancers and other gynecologic malignancies. She is one of only five OHSU faculty members to receive the Building Interdisciplinary Research Careers in Women's Health Scholar award at OHSU, and she is a member of the OHSU Center for Women's Health.  She has helped the OHSU Cancer Institute and OHSU Center for Women's Health create a multidisciplinary clinic to provide prevention strategies and treatment for women at genetic risk of ovarian and breast cancer. 

 The OHSU Cancer Institute remains the only cancer center designated by the National Cancer Institute center between Sacramento and Seattle. It comprises some 120 clinical researchers, basic scientists and population scientists who work together to translate scientific discoveries into longer and better lives for Oregon's cancer patients. In the lab, basic scientists examine cancer cells and normal cells to uncover molecular abnormalities that cause the disease. This basic science informs more than 200 clinical trials conducted at the OHSU Cancer Institute. 

The study was supported in part by grants from the National Institutes of Health, the Department of Veteran's Affairs, the Columbia River Yacht Club, and the Sherie Hildreth Ovarian Cancer Foundation.