Discovery Suggests Location of Genes for Breast Density, a Strong Risk Factor for Breast Cancer
PHILADELPHIA, Aug. 31, 2007-- ?
Studying the DNA of 889 people, gene hunters at the Mayo Clinic and
H. Lee Moffitt Cancer Centers have identified a region on
chromosome 5p that is significantly associated with dense breast
tissue, a known risk factor for breast cancer. The findings,
published in the September 1 issue of Cancer Research, a publication of the
American Association for Cancer Research, suggest that genes which
influence breast density could serve as a predictive marker for
disease and provide a biological target for agents that may reduce
breast cancer risk by reducing breast density.
Women with dense breasts – meaning the breast has a smaller
proportion of fat relative to stromal and epithelial tissues ? are
three to five times more likely to develop breast cancer than women
with less dense breasts, according to the researchers. Scientists
have estimated the total influence of genes on breast density to be
about 60 percent.
The study, the first reported genetic linkage analysis for genes
influencing breast density, “provides further evidence that
this trait does appear to be genetically influenced,” said
the study’s lead investigator, Celine Vachon, Ph.D., an
epidemiologist at the Mayo Clinic in Rochester, Minnesota.
Although the investigators have strong evidence that a gene
residing in this chromosomal region influences breast density, the
exact gene that is responsible is not yet known. “One or more
of the 45 candidate genes in this region could explain a large
proportion of mammographic breast density, and potentially, breast
cancer,” she said.
Within the region on chromosome 5p, the gene which encodes the
prolactin receptor in particular, stands out as a possible
contributor to dense breasts. Prolactin is a hormone that helps
enlarge mammary glands during pregnancy and, after childbirth, is
involved in milk production. Previous research has found a
correlation between mammographic density and prolactin levels in
postmenopausal women, the researchers note.
Vachon’s team took what they term an “agnostic”
approach to uncovering genes, or gene regulators like microRNA,
that are involved in the development of dense breasts. “We
assume we don’t know anything about the biology of the trait
and we let the genomes of our participants and their breast
densities guide us,” Vachon said.
Their method contrasts the traditional “candidate gene”
approach, where scientists look at variations in specific genes
thought to be involved with the disease or trait of interest. Such
linkage studies have been used to uncover many high-impact risk
genes, such as the breast cancer susceptibility genes BRCA1 and
BRCA2.
The Mayo researchers performed a genome-wide linkage scan to
identify possible chromosome regions in 89 families, part of a
multi-generational Minnesota family study that began in 1944 at the
University of Minnesota. Blood samples and mammograms were
collected and analyzed for 756 female participants; 133 men were
also included to help clarify genetic information in their
offspring, mothers and sisters. “We used the relationship
between family members and breast density to inform where a gene
might be,” Vachon says.
Researchers first studied 403 DNA markers spaced across the genome
to determine the amount of genetic information shared at and
between each of these genomic signposts and its correlation to
breast density as measured on mammography. They found three regions
of interest, and narrowed the most promising region further by
studying 21 additional, more densely spaced DNA markers. This
secondary analysis highlighted one region consisting of
approximately 45 known genes on chromosome 5p that was
significantly associated with increased breast density.
The researchers then adjusted their analysis to eliminate the
contribution of body mass index (BMI), which is a known breast
cancer risk factor and also inversely associated with breast
density, and found the “signal” was just as strong.
“That means the location that we have identified on
chromosome 5p does not appear to affect breast density through its
influence on BMI,” she said.
Only age, diagnosis of abnormal cells on a breast biopsy and
inheritance of rare breast susceptibility genes, such as BRCA1 and
BRCA2, are stronger risk predictors of breast cancer than is breast
density, Vachon said.
“At this point, we have not identified a gene or genes for
breast density but a promising location to investigate
further,” Vachon said. “Identification of genes for
breast density will improve our understanding of how breast density
influences breast cancer development in women.”
“In this study we focused on the genetics of a risk factor
for cancer. This approach has not been tried before,” said
Thomas Sellers, Ph.D., a coauthor on this study and currently
director of the Moffitt Research Institute in Tampa, Florida.
The study was funded by a grant from the National Cancer
Institute.
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Posted: August 2007
