DURHAM, N.C. -- A second breast cancer susceptibility gene has been located,
researchers at the Duke University Comprehensive Cancer Center and the United
Kingdom's Institute for Cancer Research reported Wednesday.
The gene, named BRCA2, likely accounts for the majority of inherited breast
cancers not caused by BRCA1, the breast cancer susceptibility gene identified
in 1994 by a team led by Mark Skolnick of the University of Utah and Myriad
Genetics Inc., according to the researchers.
The Duke and British researchers reported their findings in the Dec. 21
issue of the journal Nature. The principal investigators are P. Andrew
Futreal of Duke University Medical Center and Michael Stratton of the Institute
for Cancer Research in Surrey, England, whose laboratories collaborated
on the discovery.
"This finding means that we really are narrowing in on this dreaded
cancer," said Barbara Rimer, chairman of the National Cancer Advisory
Board and professor of community and family medicine at Duke. "But
it makes it more important than ever that we learn how to counsel women
about their options and how to develop clinics to provide support services
for the women who may carry breast cancer genes."
As with BRCA1, the researchers said they expect that women who inherit
BRCA2 may have up to an 85 percent chance of developing breast cancer.
Members of families with the BRCA2 gene also seem to be at greater risk
for several other cancers, including male breast cancer, prostate cancer
and ocular melanoma.
Unlike BRCA1, however, inheriting a defective copy of BRCA2 does not appear
to put women at a significantly greater risk of developing ovarian cancer,
although the risk is still higher than the general population, the researchers
said.
A total of 182,000 U.S. women and 29,000 women in the United Kingdom were
expected to develop breast cancer in 1995, according to estimates from the
American Cancer Society and the United Kingdom's Cancer Research Campaign.
Researchers estimated that about 5 percent of the breast cancer cases result
from inherited genetic mutations.
"BRCA1 seems to be responsible for about half of inherited breast
cancers," said Futreal, an assistant research professor of surgery
and assistant professor of genetics. "Our findings strongly suggest
that BRCA2 accounts for most of the remaining 50 percent."
With the help of physicians and scientists in five countries, Futreal and
Stratton studied a series of families with multiple cases of early-onset
breast cancer that did not have mutations in BRCA1.
Using DNA from these families, they were able to track the gene to a region
on chromosome 13. A recent finding of a pancreatic cancer with a deletion
of genetic material in the precise region of BRCA2 also aided in localizing
the region where the gene resides, Futreal said.
The inherited mutations appear to damage the cell's ability to avoid the
abnormal growth that characterizes cancer, Futreal said.
"Like BRCA1, the gene appears to function as a tumor suppressor gene,"
Futreal said. "In these families, the normal copy of the gene is knocked
out, the mutated copy is retained, and the gene loses its ability to function
normally."
The process of mapping and cloning the gene was faster this time, said
Stratton, who heads the Institute for Cancer Research's section of molecular
carcinogenesis.
"BRCA1 took four years to go from the initial mapping stage to isolation
and characterization of the specific gene involved," Stratton said.
"Due to many recent advances in molecular biology, we have managed
to shorten the process for BRCA2 to half that time."
The researchers do not yet know whether BRCA2 plays a role in the development
of sporadic, or non-inherited, breast cancers.
"Although important in increasing our understanding of breast cancer,
there are still crucial parts of the jigsaw left to piece together,"
said Gordon McVie, scientific director of the Cancer Research Campaign in
the United Kingdom. "Next, we will go on to examine both the function
of the gene and the consequences of gene damage. Simultaneously, we will
explore the role of the gene in non-family breast cancers."
Futreal has had a hand in the discovery of both breast cancer genes. As
a member of the Skolnick team, he cloned BRCA1 last year.
"The Duke Comprehensive Cancer Center is very pleased to have been
a part of the international efforts that discovered both of the breast cancer
genes," said Dr. O. Michael Colvin, director of the cancer center.
"We look forward to helping put this discovery to use as we develop
better therapies and prevention strategies to protect all women from this
disease."
Dr. Eric Winer, the co-director of Duke's multidisciplinary breast program,
said the localization of BRCA2 "paves the way for genetic testing for
both BRCA1 and BRCA2." While BRCA1 testing is not yet commercially
available, Winer and other physicians at Duke have been using a test for
that gene in an experimental program to evaluate how best to counsel at-risk
women.
Because having a mutated copy of either BRCA1 or BRCA2 could make it difficult
to obtain insurance or employment, it is important to couple testing with
counseling and support services, Rimer said.
As the medical community learns to deal with BRCA1 and BRCA2, Futreal,
Stratton and a host of other researchers will be trying to answer the many
remaining questions about hereditary breast cancers.
"Is there a BRCA3?" Futreal asked. "There is a group of
families that cannot be attributed to either BRCA1 or BRCA2. Now we need
to discover whether there is one gene, or a cluster of unrelated mutations,
behind those cancers."
The report's co-authors include researchers from Chester Beatty Laboratories,
London; the Sanger Centre, Cambs, U.K.; ICRF Clare Hall Laboratories, Potters
Bar, U.K.; the ICRF Genetic Epidemiology Laboratory, Leeds, U.K.; the University
of Cambridge and the CRC Human Cancer Genetics Research Group, Cambridge;
the University Hospital of Iceland, Reykjavik; Duke; the National Institute
of Environmental Health Sciences, Research Triangle Park, N.C.; Leiden
University, the Netherlands; Creighton University School of Medicine, Omaha,
Neb.; the International Agency for Research on Cancer, Lyon Cedex, France;
and McGill University, Montreal.
Funding for the project came from the Cancer Research Campaign, BREAKTHROUGH
Breast Cancer Charity and the Jean Rook Appeal, the Institute of Cancer
Research, the Wellcome Trust, the Medical Research Council, the Imperial
Cancer Research Fund, the U.S. Army, Duke University's Specialized Program
of Research Excellence in Breast Cancer, the National Cancer Institute,
the Icelandic Cancer Research Fund, the Nordic Cancer Union, the Dutch Cancer
Society, the Cancer Research Society, the Canadian Breast Cancer Foundation,
Ontario Chapter, the Fonds de las recherche en Sante du Quebec, the Canadian
Genetic Diseases Network and the Ligue Nationale Contre le Cancer.