Study Adds Piece to Genetic Puzzle of Ovarian Cancer

The pieces of a genetic puzzle are starting to come together. Earlier this year, University of Iowa Health Care researchers determined that a gene known as BRCA1 plays a more extensive role in ovarian cancer than previously thought. Now, they have determined the same is true for the BRCA2 gene.

The findings point to the importance of developing therapies to restore normal BRCA2 and/or BRCA1 function in women with ovarian or fallopian cancer or a related cancer known as primary peritoneal cancer. The study results appear in the Sept. 18 issue of the Journal of the National Cancer Institute.

The UI team looked for BRCA2 dysfunction in the tumors of 92 women who had been the focus of the earlier BRCA1 study. The investigators found that 82 percent of the tumors had dysfunctional BRCA1 or BRCA2.

The high incidence rate contrasts dramatically with the BRCA1 and BRCA2 dysfunction rates previously associated with ovarian cancer, said Richard Buller, M.D., Ph.D., UI professor of obstetrics and gynecology, and the study's principal investigator.

"As recently as two to three years ago, people thought only 5 to 10 percent of ovarian cancer cases had disrupted BRCA1 or BRCA2 function, and most of those dysfunctional genes were thought to be inherited," said Buller, who also is a professor of gynecologic oncology at the Holden Comprehensive Cancer Center at the UI. "However, together the two studies show frequent BRCA2 and BRCA1 dysfunction in sporadic, or non-hereditary, ovarian cancers, not just in a portion of hereditary ovarian cancers.

"With that level of dysfunction, therapies targeted toward the return of BRCA1 and BRCA2 function are very important for virtually every woman with ovarian or a related cancer," he added.

In hereditary ovarian cancer, women inherit a faulty gene, and thus their ovarian cancer often is linked to a family history of the disease. In sporadic ovarian cancer, a woman's pair of BRCA1 or BRCA2 genes initially functions well but becomes non-functional through a number of ways, including when one or both genes are lost or mutated.

When the genes function properly, they play a DNA repair and surveillance role by producing proteins that protect against tumor development. However, when one or both genes are absent or do not function properly, they produce no protein or insufficient amounts of it. The exact means by which the protein helps prevent cancer is not known.

The study also revealed an association between a defective BRCA2 gene and a cancerous condition in women who do not have ovaries. Known as primary peritoneal cancer, the disease microscopically resembles ovarian cancer but occurs instead on lining of the abdomen, not the lining of the ovaries. The investigators said that to their knowledge this was first time BRCA2 had been linked to primary peritoneal cancer.

The study also is the first to use a genetic screening test called protein truncation assay to study the BRCA2 gene. The test methodology is not new, but applying it to the entire BRCA2 gene is new, Buller said.

Even with the advances of the study, the true incidence of hereditary BRCA1 and BRCA2-related cancer still is not completely known.

"All the methods that have been used for detecting BRCA1 and BRCA2 dysfunction have limitations," Buller said. "Combining gene sequencing and protein truncation assay with other new tools and applying each method to an unselected, unbiased set of ovarian cancers would likely reveal a higher incidence rate."

Buller added that the recent UI study has limitations because it was not based on a purely random, or "unselected," sample.

Some women in the study specifically were selected because of what was known about their family history of ovarian cancer. In a random sample, women would be selected among those with ovarian cancer regardless of family history. Buller and colleagues now are studying a group of women with ovarian cancer who meet the criteria of a random sample.

In addition to Buller, Jeff Hilton, M.D., a recent graduate of the UI Roy J. and Lucille A. Carver College of Medicine, was the study's lead author. Hilton now is a resident in obstetrics and gynecology at Duke University Medical Center.

Other UI faculty and staff on the study team included John Geisler, M.D., a fellow in gynecologic oncology; Melanie Hattermann-Zogg, research assistant in Buller's lab; Jennifer Rathe, undergraduate student; and Barry DeYoung, M.D., associate professor of pathology.

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.

All the cases in the study had been diagnosed and/or treated at the Holden Comprehensive Cancer Center at the UI. The center is Iowa's only National Cancer Institute-designated comprehensive cancer center. Such 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's Web site at http://www.uihealthcare.com/depts/cancercenter.