CONTACT: BECKY SOGLIN
Iowa City IA 52242
(319) 335-6660; fax (319) 384-4638
Release: Jan. 2, 2002
BRCA1 gene role in ovarian cancer is more significant than previously
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,"
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
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
"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
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/.