Source: National Cancer Institute (NCI)
Monday, March 30, 2009

Researchers have identified new genetic variations in two regions of DNA --
located on chromosomes 1 and 14 -- that may be associated with the risk of
sporadic breast cancer. This study also confirms some of the previously
identified associations between specific regions in the genome and breast cancer
risk. The findings are reported by the Cancer Genetic Markers of Susceptibility
(CGEMS) team, which includes researchers at the National Cancer Institute
(NCI), part of the National Institutes of Health. The study appears online March
29, 2009, in Nature Genetics.

Nearly every cell in the human body contains 46 chromosomes -- tightly
packed bundles of DNA, half which came from each parent. While the DNA of any two
people is more than 99 percent the same, the fraction of DNA that varies
among individuals can play an important role in risk of disease. The most common
type of variation, called a single nucleotide polymorphism (SNP), affects
just a single building block of DNA. SNPs are used in genome-wide association
studies to identify chromosome regions that are associated with disease.

"By studying large populations of individuals with and without disease,
CGEMS research can provide powerful indicators as to which SNP variations are
associated with breast cancer," said Stephen Chanock, M.D., director of NCI's
Core Genotyping Facility and chief of the Laboratory of Translational Genomics
in the Division of Cancer Epidemiology and Genetics (DCEG). "The two new
regions identified in our study open up great possibilities for research into
novel pathways contributing to the development of breast cancer. In turn, an
in-depth understanding of the biology underlying the contribution of these
genetic variations could one day lead to new approaches for therapy or prevention
of breast cancer."

"Breast cancer is a complex disease, and it is important to recognize that
multiple genetic alterations will be involved in predicting risk and
prognosis, leading to treatment. The important next step will be to take this
association of risk and, through further research, link these specific genetic
defects to changes in biologic function," said NCI Director John E. Niederhuber,
M.D. "By understanding altered genetic pathways, we will ultimately be able to
turn knowledge of genetic variations and risk into novel targets for drug
development, which may enhance our ability to prevent and/or control this
disease."

The region identified on chromosome 1 contained the rs11249433 SNP.
Although the function of this SNP is unknown, further analysis by the CGEMS team
found that this region is predominately associated with estrogen
receptor-positive breast cancer, the most common molecular subtype of breast cancer.

The newly identified region found on chromosome 14, which included the
rs999737 SNP, is located near an interesting gene, RAD51L1, which is in a pathway
previously implicated in breast cancer risk. The protein encoded by this gene
interacts directly with those of other genes that are involved in DNA repair
and in the exchange of material between strands of DNA.

The researchers also confirmed previous reports that six other genomic
regions -- located on chromosomes 2, 5, 8, 10, and 16 -- are associated with
breast cancer risk. Further study of these regions may help to identify possible
mechanisms that may contribute to the development of breast cancer.

"We've known for over a decade about a few genes that predispose women to
risk of breast cancer," said Chanock. "But, through studies like CGEMS, we're
increasing the catalog of regions in the genome that contribute to breast
cancer risk."

In addition to Chanock, CGEMS is co-led by Joseph Fraumeni Jr., M.D.; Gilles
Thomas, M.D., Ph.D.; and Robert Hoover, M.D., Sc.D., also of NCI's DCEG;
Daniela Gerhard, Ph.D., of NCI's Office of Cancer Genomics; and David Hunter,
M.D., Sc.D., from the Harvard School of Public Health, Boston, Mass. The
success of the CGEMS project is based on a collaboration between epidemiologists,
biostatisticians, and genomic scientists at NCI and at several other research
institutions, funded through grants from NCI, who together have analyzed DNA
from thousands of cases and controls drawn from NCI-supported studies of both
breast cancer and prostate cancer.

The CGEMS team conducted a three-stage genome-wide association study in
women of European ancestry to identify SNPs that were associated with breast
cancer. Data from this CGEMS study are available to researchers through the CGEMS
data portal at <http://cgems.cancer.gov>.

Breast cancer is the second leading cause of cancer-related death in women
in the United States. Women with a family history of breast cancer are more
often diagnosed at a younger age than women who do not have relatives with the
disease, suggesting that inherited susceptibility is important in this
disease. Several genetic variations have been identified that contribute to an
inherited risk of developing breast cancer, most notably in the BRCA1 and BRCA2
genes. However, these variations account for a small fraction of breast
cancer, and it is believed that the combination of many common and
yet-to-be-identified genetic variations may contribute to increased risk.

The CGEMS team previously released similar data on prostate cancer
(www.cancer.gov/newscenter/pressreleases/CGEMSprostateUpdate), the third leading
cause of cancer-related death in men. Researchers have discovered multiple
genetic variations associated with prostate cancer risk.

For more information on NCI's Cancer Genetic Markers of Susceptibility
(CGEMS) initiative, please visit <http://cgems.cancer.gov>.

NCI leads the National Cancer Program and the NIH effort to dramatically
reduce the burden of cancer and improve the lives of cancer patients and their
families, through research into prevention and cancer biology, the development
of new interventions, and the training and mentoring of new researchers. 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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Agency -- includes 27 Institutes and Centers and is a component of the U.S.
Department of Health and Human Services. It is the primary federal agency for
conducting and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both common and rare
diseases. For more information about NIH and its programs, visit
<www.nih.gov>.
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Reference: Thomas G, Jacobs KB, Kraft P, et al. A multi-stage genome-wide
association in breast cancer identifies two novel risk alleles at 1p11.2 and
14q24.1 (RAD51L1). "Nature Genetics." Online March 29, 2009.