Breast cancer susceptibility variants and mammographic density phenotypes in norwegian postmenopausal women

Mammographic density (MD) is one of the strongest known breast cancer risk factors. Twin studies have suggested that a large part of the variation in MD is genetically determined. We hypothesized that breast cancer susceptibility variants may affect MD, and that their effects may be modified by nongenetic factors.

We assessed MD, using a computer-assisted method, on 2,348 postmenopausal Caucasian women (50-69 years) who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004 or 2006-07. We used linear regression (additive models) to determine the association between each SNP and MD, adjusting for age, body mass index (BMI), and study. We evaluated MD associations with 17 established breast cancer SNPs, overall, and by strata defined by non-genetic factors.

Two variants, 6q25.1-rs9383938 and TXNRD2-rs8141691, were statistically significantly associated with percent MD (P = 0.019 and 0.03, respectively), with the 6q25.1-rs9383938 association being consistent with the SNP effect on breast cancer risk. The effect of 6q25.1-rs3734805 on percent MD varied between parous and nulliparous women (Pinteraction = 0.02), whereas the effects of 9q31.2-rs865686 and MRPS30:FGF10-rs4415084 differed across strata of BMI (Pinteraction = 0.01 and 0.005, respectively). There was no evidence of effect modification by estrogen and progestin therapy use or alcohol consumption.

This study provides novel evidence of shared genetic risk factors between MD and breast cancer and of possible MD genetic-environmental interactions.

Although the results may be chance findings, they nevertheless highlight the need to investigate interactions with nongenetic factors in studies on the genetics of MD.