Genetic Aspects of Mammographic Density Measures Associated with Breast Cancer Risk

Cumulus, Altocumulus, and Cirrocumulus are measures of mammographic density defined at increasing pixel brightness thresholds, which, when converted to mammogram risk scores (MRSs), predict breast cancer risk. Twin and family studies suggest substantial variance in the MRSs could be explained by genetic factors. For 2559 women aged 30 to 80 years (mean 54 years), we measured the MRSs from digitized film mammograms and estimated the associations of the MRSs with a 313-SNP breast cancer polygenic risk score (PRS) and 202 individual SNPs associated with breast cancer risk. The PRS was weakly positively correlated (correlation coefficients ranged 0.05−0.08; all p < 0.04) with all the MRSs except the Cumulus-white MRS based on the “white but not bright area” (correlation coefficient = 0.04; p = 0.06). After adjusting for its association with the Altocumulus MRS, the PRS was not associated with the Cumulus MRS. There were MRS associations (Bonferroni-adjusted p < 0.04) with one SNP in the ATXN1 gene and nominally with some ESR1 SNPs. Less than 1% of the variance of the MRSs is explained by the genetic markers currently known to be associated with breast cancer risk. Discovering the genetic determinants of the bright, not white, regions of the mammogram could reveal substantial new genetic causes of breast cancer.