CONTACT: BECKY SOGLIN
2130 Medical Laboratories
Iowa City IA 52242
(319) 335-6660; fax (319) 335-8034
Release: Oct. 20, 1999
UI study: certain genetic abnormality may predict ovarian
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
studys 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
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.
Bullers 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,"
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.