|Newly Identified Genetic Variations May Affect
Breast Cancer Risk
Researchers have identified genetic variations in a region of
DNA that may be associated with risk for breast cancer. Women with
the variation have a 1.4 times greater risk of developing breast
cancer compared to those without this variation. The study is one
of several genome-wide association studies looking for breast cancer
genes to be published this year by researchers at the National
Cancer Institute (NCI), part of the National Institutes of Health,
and their colleagues. These findings appeared online in the Proceedings
of the National Academy of Sciences on March 3, 2008.
"A genome-wide association study looks at the entire genome
for a type of genetic variation that occurs more frequently in
people who have a certain disease than in similar people who do
not have the disease," said Bert Gold, Ph.D., of NCI's Center
for Cancer Research, the study's lead author. "Using this
research approach, we found variations in a gene locus, a specific
place on a chromosome where a gene is located, that had not been
identified in previous studies."
Genome-wide association studies look for genetic variations known
as single nucleotide polymorphisms (SNP). SNPs are alterations
in the genetic code in which a single nucleotide — the individual
building blocks that make up DNA — is changed. The researchers
found that variations in four SNPs located in a region of chromosome
6 were present more often in the breast cancer patients, suggesting
that genes in this region might contribute to the risk of breast
cancer. The researchers also confirmed the finding of previous
studies indicating that the locus named FGFR2 is associated
with a 20 percent increased risk of breast cancer.
"The likelihood that this finding could be due to chance
alone is about one in 300 million," said Gold. "We have
already begun experiments to try to identify the genes associated
with risk, and then try to characterize their function. It is hoped
that identifying the genes responsible for this increased risk
may lead to new therapies that target the actions of these genes."
"Progressing from genome-wide association studies to the
development of therapies and enhanced diagnostic techniques based
on those findings will require continued, sustained effort from
laboratory researchers who will unite our newfound knowledge of
the genome with the study of cancer biology," said NCI Director
John E. Niederhuber, M.D.
Several genes located in this chromosome region play a role in
regulating important cell processes, such as cell cycle, DNA replication
and repair, cell signaling, and programmed cell death. Defects
in these processes have been well documented in breast cancer.
While the variations in chromosome 6 that increase risk for breast
cancer were found in 23 percent of the women studied, their risk
of developing breast cancer is relatively small compared to the
high-risk associated with BRCA gene mutations. BRCA genes
were identified in the 1990s and mutations in these genes are among
the strongest known genetic risk factors for breast cancer. The
researchers estimate that only about seven percent of breast cancer
cases in this current study could be attributed to the locus they
found on chromosome 6.
"Although identifying individual low risk loci may have
limited clinical implications, it is not known whether interactions
among multiple loci will put a woman at greater risk of developing
breast cancer," said Gold. "A better understanding of
the genetic mutations that contribute to breast cancer is likely
to come from the identification of these low risk variants and
from studies that investigate the mechanisms underlying their associations."
The researchers conducted a three-phase genome-wide association
study to look for SNPs that may be associated with breast cancer
risk. In the first phase, they analyzed more than 150,000 SNPs
in DNA samples obtained from 249 Ashkenazi Jewish women who had
breast cancer and a family history of the disease but did not carry
the BRAC1 or BRAC 2 mutation and from 299 Ashkenazi Jewish
women who had not developed cancer. They studied Ashkenazi Jewish
women because many studies have demonstrated that this population
has been associated with an increased breast cancer risk compared
to other populations. In the next two phases, the researchers verified
their findings in 950 Ashkenazi Jewish women with breast cancer
and 979 Ashkenazi Jewish women who did not have cancer as well
as in a set of 243 Ashkenazi Jewish women who had sporadic breast
cancer and 187 cancer-free Ashkenazi Jewish women.
The study participants indicated that all four of their grandparents
were Jewish and of Eastern European descent. The study was designed
and directed by a research team at Memorial Sloan-Kettering Cancer
Center in New York, with participation from other centers in the
United States, Canada, and Israel. In addition to the study coordinating
center at Memorial Sloan-Kettering, this study was a collaboration
between the NCI and researchers at Memorial Sloan-Kettering Cancer
Center, New York, N.Y., Dana-Farber Cancer Institute, Boston, Mass.,
Tel-Aviv University, Tel-Aviv, Israel, Centre for Research in Women's
Health, Toronto, Canada, North Shore Long Island Jewish Research
Institute, Manhasset, N.Y., SAIC-Frederick, Inc., Frederick, Md.,
University of Chicago, Chicago, Ill., Cornell University, Ithaca,
N.Y., and Memorial Health University Medical Center, Anderson Cancer
Institute, Savannah, Ga.
For more information on research in Dr. Gold's group, please go
For more information about cancer, please visit the NCI website
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's
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,
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.
Gold B, Kirchhoff T, Stefanov S, Lautenberger J, Viale A, Garber
J, Friedman E, Narod S, Olshen A, Gregersen P, Kosarin K, Olsh A,
Bergeron J, Ellis N, Klein RJ, Clark AG, Norton L, Dean M, Boyd J,
and Offit K. March 2008. Genome Wide Association Study Provides Evidence
for a Breast Cancer Risk Locus at 6q22.23. PNAS. Online
March 3, 2008.