Hopeful
09-14-2007, 06:20 AM
Jacquelyn K. Beals <!-- /If AUTHOR -->
Medscape Medical News 2007. © 2007 Medscape
<!-- /POST TITLE -->
<!-- Main Table -->September 13, 2007 — A recent study reveals the location of a gene that influences mammographic density (MD), the proportion of breast tissue that appears dense on a mammogram. The study, in the September 1 issue of Cancer Research, reports the results of the first genome-wide linkage scan to focus on genes that influence breast tissue density.
Study participants were drawn from 426 multigenerational families, each with a breast cancer proband diagnosed from 1944 to 1952 at the University of Minnesota. Narrowed to families that would be most informative for linkage analysis studies, the final sample consisted of 89 families for a total of 889 individuals (133 male, 756 female), all white.
"The benefit of [a family study] is that people are related and you're basically not making any assumptions about the underlying biology of the trait," explained author Celine Vachon, PhD, from the Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, in a phone interview with Medscape. "You're saying, 'Can I find any regions that might be evidence for a gene for breast density, just using the relatedness among individuals regarding the underlying blood markers on the DNA?' "
Study participants provided DNA through blood or buccal samples, and women permitted access to their most recent mammogram for digitization.
Proportion vs Total Amount of Dense Tissue?
One challenge of interpreting MD is the fact that mammograms are 2-dimensional images of 3-dimensional structures.
"A few groups...have been trying to get an estimate of volumetric density," said Dr. Vachon. "You need some kind of standard on each mammogram so you know each pixel intensity, so you're making some inference about what each means.... Nobody as yet has shown that the volumetric measure is predictive of risk."
The introduction of full-field digital tomography, which enables 3-dimensional breast imaging, will help determine the volume of dense tissue, rather than its proportion. "It's the next step...and incorporating a volumetric measure will be easier to do," said Dr. Vachon.
However, as Thomas A. Sellers, PhD, MPH, from the Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, and coauthor of this study, told Medscape in an email: "If it's the dense tissue that is underlying the differences in breast cancer risk...then the totalamount of dense tissue would be a stronger predictor of risk than the relativeamount. Our group and others have shown that this is not true: percent density is a stronger predictor than absolute amount of dense tissue."
Covariates and Genetic Linkage of MD
The Cancer Research study found that MD is positively associated with premenopausal status, nulliparity, number of years of oral contraceptive (OC) use, current OC and hormone therapy use, lifetime alcohol consumption, and education; MD is inversely associated with body mass index (BMI) and age. The latter 2 factors explained the greatest MD variability.
"Most of us consider MD as an indicator of underlying processes," commented Giske Ursin, MD, PhD, associate professor of preventive medicine from the Keck School of Medicine, University of Southern California, Los Angeles, whose research also focuses on breast cancer risk factors. In an email to Medscape, she noted: "Higher MD represents more epithelial cells, more collagen — and thus more proliferative activity.... Although we have no evidence of the clinical significance of a MD increase yet, I would be concerned about any type of hormone treatments that results in a large increase in MD."
Linkage analyses were run for mean MD both with and without adjusting for BMI and for BMI both with and without adjusting for MD. A region on the short arm of chromosome 5 (5p) showed the strongest linkage with MD but fell short of statistical significance (log odds for linkage [LOD] scores > 3.3 are significant). Two regions on chromosome 12 also demonstrated possible linkage with MD. Although MD and BMI show high genetic correlation (0.71), the linkage results for chromosomes 5 and 12 were the result of mean MD and not BMI.
Fine mapping of the 5p region yielded statistically significant support for linkage (LOD = 4.2). The study concluded that this 5p locus may account for as much as 22% of the total variability in mean MD.
It is very likely that at least 1 gene on chromosome 5p influences MD. Identifying this gene could lead researchers to new genes for breast cancer and new targets for the reduction of density. Meanwhile, Dr. Sellers recommends: "For women with greater [MD] levels, it would be even more incumbent on the physician to recommend regular mammography."
Dr. Vachon, Dr. Sellers, and Dr. Ursin report no relevant financial relationships.
Cancer Res. 2007;67(17):8412–8418
Hopeful
Medscape Medical News 2007. © 2007 Medscape
<!-- /POST TITLE -->
<!-- Main Table -->September 13, 2007 — A recent study reveals the location of a gene that influences mammographic density (MD), the proportion of breast tissue that appears dense on a mammogram. The study, in the September 1 issue of Cancer Research, reports the results of the first genome-wide linkage scan to focus on genes that influence breast tissue density.
Study participants were drawn from 426 multigenerational families, each with a breast cancer proband diagnosed from 1944 to 1952 at the University of Minnesota. Narrowed to families that would be most informative for linkage analysis studies, the final sample consisted of 89 families for a total of 889 individuals (133 male, 756 female), all white.
"The benefit of [a family study] is that people are related and you're basically not making any assumptions about the underlying biology of the trait," explained author Celine Vachon, PhD, from the Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, in a phone interview with Medscape. "You're saying, 'Can I find any regions that might be evidence for a gene for breast density, just using the relatedness among individuals regarding the underlying blood markers on the DNA?' "
Study participants provided DNA through blood or buccal samples, and women permitted access to their most recent mammogram for digitization.
Proportion vs Total Amount of Dense Tissue?
One challenge of interpreting MD is the fact that mammograms are 2-dimensional images of 3-dimensional structures.
"A few groups...have been trying to get an estimate of volumetric density," said Dr. Vachon. "You need some kind of standard on each mammogram so you know each pixel intensity, so you're making some inference about what each means.... Nobody as yet has shown that the volumetric measure is predictive of risk."
The introduction of full-field digital tomography, which enables 3-dimensional breast imaging, will help determine the volume of dense tissue, rather than its proportion. "It's the next step...and incorporating a volumetric measure will be easier to do," said Dr. Vachon.
However, as Thomas A. Sellers, PhD, MPH, from the Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, and coauthor of this study, told Medscape in an email: "If it's the dense tissue that is underlying the differences in breast cancer risk...then the totalamount of dense tissue would be a stronger predictor of risk than the relativeamount. Our group and others have shown that this is not true: percent density is a stronger predictor than absolute amount of dense tissue."
Covariates and Genetic Linkage of MD
The Cancer Research study found that MD is positively associated with premenopausal status, nulliparity, number of years of oral contraceptive (OC) use, current OC and hormone therapy use, lifetime alcohol consumption, and education; MD is inversely associated with body mass index (BMI) and age. The latter 2 factors explained the greatest MD variability.
"Most of us consider MD as an indicator of underlying processes," commented Giske Ursin, MD, PhD, associate professor of preventive medicine from the Keck School of Medicine, University of Southern California, Los Angeles, whose research also focuses on breast cancer risk factors. In an email to Medscape, she noted: "Higher MD represents more epithelial cells, more collagen — and thus more proliferative activity.... Although we have no evidence of the clinical significance of a MD increase yet, I would be concerned about any type of hormone treatments that results in a large increase in MD."
Linkage analyses were run for mean MD both with and without adjusting for BMI and for BMI both with and without adjusting for MD. A region on the short arm of chromosome 5 (5p) showed the strongest linkage with MD but fell short of statistical significance (log odds for linkage [LOD] scores > 3.3 are significant). Two regions on chromosome 12 also demonstrated possible linkage with MD. Although MD and BMI show high genetic correlation (0.71), the linkage results for chromosomes 5 and 12 were the result of mean MD and not BMI.
Fine mapping of the 5p region yielded statistically significant support for linkage (LOD = 4.2). The study concluded that this 5p locus may account for as much as 22% of the total variability in mean MD.
It is very likely that at least 1 gene on chromosome 5p influences MD. Identifying this gene could lead researchers to new genes for breast cancer and new targets for the reduction of density. Meanwhile, Dr. Sellers recommends: "For women with greater [MD] levels, it would be even more incumbent on the physician to recommend regular mammography."
Dr. Vachon, Dr. Sellers, and Dr. Ursin report no relevant financial relationships.
Cancer Res. 2007;67(17):8412–8418
Hopeful