Researchers Identify Genetic Variations
That May Increase Risk of Breast Cancer
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 NCIís 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.
"Weíve known for over a decade about a few genes that predispose
women to risk of breast cancer," said Chanock. "But,
through studies like CGEMS, weíre 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 NCIís DCEG; Daniela Gerhard, Ph.D., of NCIís 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 www.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
the third leading cause of cancer-related death in men. Researchers
have discovered multiple genetic variations associated with prostate
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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Medical Research 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,
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its programs, visit www.nih.gov.
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.