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Release: Oct. 20, 1999

UI study: certain genetic abnormality may predict ovarian cancer spread

IOWA CITY, Iowa -- Nearly 20 percent of women treated for ovarian cancer develop other tumors beyond the abdomen. Until recently, researchers have focused on prolonged survival or treatment of the disease as causes of these distant metastases. However, a specific type of mutation on the p53 tumor suppressor gene may predispose some women with ovarian cancer to distant -- and rapid -- tumor spread, according to a University of Iowa Health Care study.

"We knew that some women with ovarian cancer rapidly develop metastases to the liver, lungs or other distant sites, and that p53 is one of the most commonly mutated genes associated with ovarian cancer," said Anil K. Sood, UI assistant professor of obstetrics and gynecology, and author of the study published in the September issue of the journal Clinical Cancer Research. "So we investigated whether different types of p53 mutations predispose women with ovarian cancer to developing more aggressive tumors. We found that distant metastases were almost eight times more likely in patients whose tumors had a ‘null’ mutation compared to other mutations."

Richard E. Buller, M.D., Ph.D., UI professor of obstetrics and gynecology and director of the gynecologic oncology division, was the study’s lead investigator. He has studied ovarian cancer and genetic mutations for nearly a decade.

"It is important to identify specific gene changes in ovarian cancer that correlate with clinical behavior and can be selectively targeted with novel therapeutic strategies such as gene therapy," Buller said. "This study basically shows that not all p53 gene mutations are created equal and that shortened p53 protein is probably nonfunctional, whereas a simple amino acid change in the p53 protein allows it to help keep ovarian cancer within the abdomen."

The lack of functional p53 protein may cause an imbalance in factors that control angiogenesis, the development of new blood vessels. As a result, tumor growth cannot be suppressed, and the cancer spreads, Sood said.

The investigators screened for the p53 mutations by examining 130 tumor DNA sequences taken from women (ages 31 to 89) with ovarian cancer. A total of 28 patients had distant metastases, primarily to the liver. When correlated with the three types of mutations, the researchers found that 21 of 33 patients (66 percent) with a null mutation of p53 developed distant metastases. In contrast, tumors had spread beyond the abdomen in only 3 of 36 (8 percent) patients with a normal gene and 5 of 62 women (8 percent) with a missense mutation, a minor alteration that still allows tumor-suppressing protein to be made.

The null mutation was also more likely to cause rapid development of distant metastases -- in 1.18 years, compared to 2.71 years for the missense mutation and 3.57 years for the normal gene.

"It has been thought that distant metastases of ovarian cancer result from prolonged survival or that chemotherapy alters mechanisms that prevent distant metastases," Sood said. "However, our findings challenge these beliefs because some women had distant tumors upon initial presentation or developed them rapidly."

Sood said the study results may eventually help physicians use p53 mutation analysis to make prognoses about ovarian cancer progression in patients. Patients who might develop distant metastases due to a p53 null mutation could receive more aggressive therapies that target the whole body, not just the abdomen, or new treatments such as gene therapy.

Buller’s research team is now studying how different p53 mutations affect patients’ survival.

"A direct application of this work is a phase II/III clinical trial at the UI Hospitals and Clinics in which normal p53 genes are transferred back into ovarian cancer cells in an attempt to destroy these cells more effectively when conventional chemotherapy is given," Buller said.

Ovarian cancer is the fifth most common cancer in women and the most deadly of all gynecological cancers. A pap smear, which can detect cervical cancer, usually is an ineffective screen for ovarian cancer, which produces vague symptoms.

The study was supported in part by funding Buller received from an American Cancer Society Institutional Seed Grant and by an academic training fellowship that Sood received from the American College of Obstetricians and Gynecologists-Ortho. In addition to Buller and Sood, other investigators from the UI Division of Gynecologic Oncology were Joel I. Sorosky, M.D., professor of obstetrics and gynecology; Barrie Anderson, M.D., professor of obstetrics and gynecology; and Marisa Dolan, research assistant and UI College of Pharmacy student, who was a UI undergraduate student researcher at the time of the study.

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.