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Epidemiology and Prevention |
Departments of 1 Health Sciences Research and 2 Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota; and 3 H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Requests for reprints: Celine M. Vachon, Department of Health Sciences Research, Charlton 6-239, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: 507-284-9977; Fax: 507-266-2478; E-mail: vachon.celine{at}mayo.edu.
Increased mammographic density (MD), the proportion of dense tissue visible on a mammogram, is a strong risk factor for breast cancer, common in the population and clusters in families. We conducted the first genome-wide linkage scan to identify genes influencing MD. DNA was obtained from 889 relatives (756 women, 133 men) from 89 families. Percent MD was estimated on 618 (82%) female family members using a validated computer-assisted thresholding method. The genome-wide scan included 403 microsatellite DNA markers with an average spacing of 9 cM. Fine mapping of a region of chromosome 5p (5p13.1-5p15.1) was done using 21 additional closely spaced DNA markers. Linkage analyses were conducted to quantify the evidence for a gene responsible for MD across the genome. The maximum log odds for linkage (LOD) score from the genome-wide scan was on chromosome 5p (LOD = 2.9, supporting linkage by a factor of 102.9 or 794 to 1) with a 1-LOD interval spanning 28.6 cM. Two suggestive regions for linkage were also identified on chromosome 12 (LOD = 2.6, 1-LOD interval of 14.8 cM; and LOD = 2.5, 1-LOD interval of 17.2 cM). Finer mapping of the region surrounding the maximum LOD on chromosome 5p resulted in stronger and statistically significant evidence for linkage (LOD = 4.2) and a narrowed 1-LOD interval (13.4 cM). The putative locus on chromosome 5p is likely to account for up to 22% of variation in MD. Hence, 1 or more of the 45 candidate genes in this region could explain a large proportion of MD and, potentially, breast cancer. [Cancer Res 2007;67(17):8412–8]
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