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Release: Jan. 2, 2002

BRCA1 gene role in ovarian cancer is more significant than previously thought

IOWA CITY, Iowa -- BRCA1 gene dysfunction in women with ovarian cancer is more common than previously thought and occurs with greater frequency through ways other than inheriting a defective copy of the gene, according to a University of Iowa Health Care study.

The investigation used a new screening strategy that can effectively detect different underlying causes of abnormally functioning BRCA1 genes in women already diagnosed with ovarian cancer. The findings have implications for increased understanding of ovarian cancer and the eventual development of therapies that could target the defective gene. The study results appear in the Jan. 2 issue of the Journal of the National Cancer Institute (NCI).

The UI team found that 23 percent, or nearly one in four, of 221 ovarian cancer cases had dysfunction in BRCA1 due to one of several mechanisms, not just inherited gene defects, said Richard Buller, M.D., Ph.D., UI professor of obstetrics and gynecology, and the study's principal investigator. Previous research had shown that only 5 to 6 percent of all ovarian cancers were due to BRCA1 genes that did not function properly, and the problematic genes often were linked to a family history of ovarian cancer.

"The study showed that a larger proportion of women with ovarian cancer has some degree of BRCA1 dysfunction than was previously thought -- by a factor of up to five times as much," said Buller, who also is director of gynecologic oncology with the Holden Comprehensive Cancer Center at the UI. "The fact that we found so many BRCA1 abnormalities through the new screening strategy identifies the BRCA1 gene as a target for new therapeutic strategies.

"As a search tool, the screen found that family history is relatively unimportant in looking for BRCA1 genes that aren't working properly," he added.

The screening method is not a diagnostic tool for common use in the doctor's office. Instead, it will help researchers better understand BRCA1-related ovarian cancers in women already diagnosed with tumors. The screen is more sensitive, efficient and cost-effective than previous BRCA1 gene screening methods.

Buller said that technological advances increased the team's ability to find mutations that previous technologies had missed. Combining methods developed by others, Buller's team developed a three-part screening method.

The first step in the screen is to see if one of the two BRCA1 gene copies is missing. A missing copy may indicate abnormal BRCA1 function.

"Now we know that loss of one of the genes is actually a better search tool for screening than just taking a family history," Buller said. "We can flag a larger segment of the population who has ovarian cancer instead of studying only the 5 to 10 percent of the cases developing in families with lots of cases of breast and ovarian cancer."

The second screening step, called protein truncation, looks for errors in the gene code that result in a shortened or nonfunctional protein product. The third step identifies cancers that do not make any BRCA1 mRNA and, therefore, cannot make any BRCA1 protein.

Depending on the results from the three tests, the researchers could determine whether the BRCA1 gene problems were due to gene silencing or mutation. When it functions normally, BRCA1 helps to keep tumors from developing. However, its exact function is not known.

"We don't know exactly what BRCA1 does but we do know that it generally behaves like a tumor-suppressor," Buller said. "So when its function is lost it's easier for an individual to develop a cancer, particularly breast or ovarian cancer."

Buller explained there are three ways that BRCA1 can have an abnormal function.

"First, an inherited gene defect in BRCA1 can cause hereditary disease," he said. "Second, two normal copies of the gene can be inherited but one later mutates while the other copy of the gene is lost. That results in a proportion of the sporadic ovarian cancers -- those cancers which are not inherited.

"Third, the BRCA1 function can be completely eliminated if you lose one copy of the gene and the other copy gets shut down, or if both copies get turned off. These losses can happen without any mutations," Buller said.

In addition to Buller, the study team included primary author John P. Geisler, M.D., a UI fellow in gynecologic oncology; Melanie Hatterman-Zogg, UI research assistant in Buller's lab; and Jennifer Rathe, a UI undergraduate student.

The study was funded in part by a Florence and Marshall Schwid Award from the Gynecologic Cancer Foundation and by a Public Health Service (PHS) grant to Buller as well as a PHS training grant to Geisler. Both PHS grants are from the National Cancer Institute.

The Holden Comprehensive Cancer Center is Iowa's only National Cancer Institute-designated comprehensive cancer center. NCI-designated comprehensive cancer centers are recognized as the leaders in developing new approaches to cancer prevention and cancer care, conducting leading edge research and educating the public about cancer. Visit the center online at http://www.uihealthcare.com/depts/cancercenter.

University of Iowa Health Care describes the partnership between the UI College of Medicine and the UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at http://www.uihealthcare.com/.