title: Strong evidence of a genetic determinant for mammographic density, a major risk factor for breast cancer.
abstract: 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 10(2.9) 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.
authors.affiliation: Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. vachon.celine@mayo.edu
authors.forename: Celine M
authors.initials: CM
authors.lastname: Vachon
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
authors.forename: Erin E
authors.initials: EE
authors.lastname: Carlson
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hilker
authors.forename: Regenia L
authors.initials: RL
authors.lastname: Smalley
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Linda E
authors.initials: LE
authors.lastname: Kelemen
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000473:pathology*; D002452:Cell Count; D002874:Chromosome Mapping; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008126:Lod Score; D008297:Male; D008327:Mammography; D008875:Middle Aged; D012307:Risk Factors; D014463:Ultrasonography