Associations between breast density and a panel of single nucleotide polymorphisms linked to breast cancer risk: a cohort study with digital mammography

Abstract

Background: Breast density and single-nucleotide polymorphisms (SNPs) have both been associated with breast cancer risk. To determine the extent to which these two breast cancer risk factors are associated, we investigate the association between a panel of validated SNPs related to breast cancer and quantitative measures of mammographic density in a cohort of Caucasian and African-American women.

Methods: In this IRB-approved, HIPAA-compliant study, we analyzed a screening population of 639 women (250 African American and 389 Caucasian) who were tested with a validated panel assay of 12 SNPs previously associated to breast cancer risk. Each woman underwent digital mammography as part of routine screening and all were interpreted as negative. Both absolute and percent estimates of area and volumetric density were quantified on a per-woman basis using validated software. Associations between the number of risk alleles in each SNP and the density measures were assessed through a race-stratified linear regression analysis, adjusted for age, BMI, and Gail lifetime risk.

Results: The majority of SNPs were not found to be associated with any measure of breast density. SNP rs3817198 (in LSP1) was significantly associated with both absolute area (p = 0.004) and volumetric (p = 0.019) breast density in Caucasian women. In African-American women, SNPs rs3803662 (in TNRC9/TOX3) and rs4973768 (in NEK10) were significantly associated with absolute (p = 0.042) and percent (p = 0.028) volume density respectively.

Conclusions: The majority of SNPs investigated in our study were not found to be significantly associated with breast density, even when accounting for age, BMI, and Gail risk, suggesting that these two different risk factors contain potentially independent information regarding a woman's risk to develop breast cancer. Additionally, the few statistically significant associations between breast density and SNPs were different for Caucasian versus African American women. Larger prospective studies are warranted to validate our findings and determine potential implications for breast cancer risk assessment.

Figure 1

Area-density segmentations on right, mediolateral-oblique view mammograms for various SNP genotypes. Four Caucasian women with negative screening exams and different genotypes of rs3817198 in LSP1 (a,b) and rs1045485 in CASP8 (c,d). Mammograms in the left column (a,c) represent women who are homozygous for the common allele for each SNP, while mammograms in the right column (b,d) are from women who are homozygous for the risk allele for each SNP. Overall, SNPs, age, Gail life-time risk and BMI were found to only explain a small fraction of the variability in breast density between women. For reference, each woman’s age and overall PD% score are provided as annotations on each image.

Figure 2

Box plots illustrating the distribution of breast density measures to significantly associated SNP genotypes. a) Absolute dense tissue area versus SNP rs3817198 in Caucasian women; b) Absolute volume of dense tissue versus SNP rs3817198 in Caucasian women; c) Absolute volume of dense tissue versus SNP rs3803662 in African-American women; and d) Percent volumetric density (VD%) versus SNP rs4973768 in African-American women. All box plots provide the median (red-line), interquartile range (blue box), 95% confidence interval (black whiskers) and outliers beyond the 95% confidence interval (red plus-signs).