Strong evidence of a genetic determinant for mammographic density, a major risk factor for breast cancer

Celine M Vachon, Thomas A. Sellers, Erin E. Carlson, Julie M Cunningham, Christopher A. Hilker, Regenia L. Smalley, Daniel J Schaid, Linda E. Kelemen, Fergus J Couch, V. Shane Pankratz

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)8412-8418
Number of pages7
JournalCancer Research
Volume67
Issue number17
DOIs
StatePublished - Sep 1 2007

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Breast Neoplasms
Chromosomes
Genome
Genetic Markers
Genes
Chromosomes, Human, Pair 12
Microsatellite Repeats
Breast Density
DNA
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Strong evidence of a genetic determinant for mammographic density, a major risk factor for breast cancer. / Vachon, Celine M; Sellers, Thomas A.; Carlson, Erin E.; Cunningham, Julie M; Hilker, Christopher A.; Smalley, Regenia L.; Schaid, Daniel J; Kelemen, Linda E.; Couch, Fergus J; Pankratz, V. Shane.

In: Cancer Research, Vol. 67, No. 17, 01.09.2007, p. 8412-8418.

Research output: Contribution to journalArticle

Vachon, Celine M ; Sellers, Thomas A. ; Carlson, Erin E. ; Cunningham, Julie M ; Hilker, Christopher A. ; Smalley, Regenia L. ; Schaid, Daniel J ; Kelemen, Linda E. ; Couch, Fergus J ; Pankratz, V. Shane. / Strong evidence of a genetic determinant for mammographic density, a major risk factor for breast cancer. In: Cancer Research. 2007 ; Vol. 67, No. 17. pp. 8412-8418.
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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 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.",
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AU - Smalley, Regenia L.

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AU - Pankratz, V. Shane

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