|Variation in a Gene May Help Protect against
A large-scale analysis of data on breast cancer risk has concluded
that a common variation in the gene caspase-8 (CASP8) is
associated with a somewhat lower risk of the disease. Variants
are small changes that occur in a gene sequence. The results are
from the second study published by the Breast Cancer Association
Consortium (BCAC), which includes researchers at the National Cancer
Institute (NCI), part of the National Institutes of Health (NIH).
“The consortium, which was launched in 2005, has helped speed
the discovery of genes and variants involved in breast cancer through
the pooling of data from many studies and should prove invaluable
to future research studies that explore the genetic aspects of
cancer,” said NIH Director Elias A. Zerhouni, M.D.
The results were published in the February 11, 2007 issue of Nature
Genetics*. “This study demonstrates
how genes that confer modest effects on breast cancer risk can
be identified when sufficiently large data sets are assembled,” said
NCI Director John E Niederhuber, M.D. “Analyses of this type
should help accelerate our ability to target the right genes
for very specific subsets of disease.”
Mutations in genes with large effects on breast cancer risk have
been identified, yet most single population-based studies lack
the statistical power to detect more common variations in genes
that contribute only small amounts to breast cancer risk. To confirm
a previously identified association with a variant of the CASP8 gene,
for example, the Consortium used data on 33,000 women from 14 studies.
The researchers say that the new findings have no immediate implications
for women. “But using the same approach we may be able, in the
future, to identify a panel of variants with small increases in
risk that collectively may put a woman at a much higher risk,” says
Montserrat Garcia-Closas, M.D., Dr.P.H., of NCI’s Division of Cancer
Epidemiology and Genetics and one of the study’s lead authors.
“This study provides proof of principle that consortia like the
BCAC are valuable for understanding the contributions of genetic
factors in complex diseases. A better understanding of the biology
of breast cancer is likely to come from the identification of these
variants and future studies that investigate the mechanisms underlying
the associations,” she adds.
To date, the BCAC has evaluated about 20 single nucleotide polymorphisms
(SNPs), the most common type of gene variant in which a single
unit of DNA may vary from one person to the next. Each SNP investigated
has been linked to breast cancer risk by at least two studies that
included more than 10,000 individuals. The BCAC uses essentially
all the available data on a SNP, including unpublished results,
to either confirm or refute an association.
Two previous studies suggested that a SNP in CASP8, called
D302H, is associated with a reduction in breast cancer risk. The
researchers caution that population-based data alone cannot prove
that this particular variant is responsible for the association.
Other studies are underway to determine whether D302H or another
variant nearby might be responsible.
Most of the 14 studies that contributed data to the Consortium’s
analysis included women of predominantly white European ancestry.
The variant is estimated to be present in 13 percent of white women
of European descent. (The variant was not present in two Asian
populations studied.) Garcia-Closas said that, based on this study,
researchers will likely assess the D302H polymorphism and other
variants in the CASP8 gene in other ethnic groups.
Future studies will also investigate the biology of how variation
in this gene may protect against the disease. The protein produced
by the CASP8 gene participates in programmed cell death,
or apoptosis, a defense mechanism that allows cells to commit suicide
rather than develop into a tumor. DNA damage can trigger apoptosis,
and one hypothesis is that the CASP8 SNP may enhance the
body’s ability to clear cancerous cells from the body and thereby
lower the risk of breast cancer.
While mutations in some genes such as BRCA1 have previously been
linked to cancer risk, the genetic variation found in the CASP8
gene is the first common variant to be definitively associated
with breast cancer risk. In addition to this variant, the study
found some support for an association with breast cancer risk for
a variant in the gene TGFB1(Transforming Growth Factor
Beta 1). Numerous other variants are likely to be identified in
the coming years from genome-wide association studies, said Jeffery
P. Struewing, M.D., senior investigator in the Laboratory of Population
Genetics at NCI’s Center for Cancer Research and a coauthor of
the current study.
Effective strategies for finding variants in genes that contribute
modestly to breast cancer risk are needed. Mutations in genes such
as BRCA1 or BRCA2 account for less than 25 percent
of the excess familial risk of breast cancer. Much of the remaining
variation in genetic risk is likely to be explained by the cumulative
effect of multiple variants in genes that individually confer relatively
small amounts of risk.
“The SNPs in CASP8, and perhaps in TGFB1, are
the first examples of such variants,” said Douglas F. Easton, Ph.D.
of Cancer Research United Kingdom Genetic Epidemiology Unit, one
of the leaders of the BCAC. “Given that only a small number of
genes have been investigated in this depth, the results suggest
that large numbers of breast cancer susceptibility variants will
eventually be found.”
The first results published by the BCAC appeared in the October
4, 2006 issue of the Journal of the National Cancer Institute.
For more information on Dr. Struewing’s research, go to http://ccr.cancer.gov/staff/staff.asp?profileid=5540.
For more information about cancer, please visit the NCI Web site
at http://www.cancer.gov, or
call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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