Familial Aspects of Mammographic Density Measures Associated with Breast Cancer Risk

SIMPLE SUMMARY: Cumulus, Cumulus-percent, Altocumulus, Cirrocumulus, and Cumulus-white are mammogram risk scores (MRSs) that predict a woman’s risk of breast cancer based on mammographically dense areas when defined by different levels of brightness. We measured these MRS for 593 monozygotic (MZ) and 326 dizygotic (DZ) female twin pairs and 1592 of their sisters. We estimated how much these MRSs were correlated in relatives (ρ), how much of the differences between women were due to genetic factors (heritability), and how much these MRS explained why breast cancer runs in families. The ρ estimates ranged from: 0.41 to 0.60 for MZ pairs, 0.16 to 0.26 for DZ pairs, and 0.19 to 0.29 sister pairs, respectively. Heritability estimates were 36% to 69%. Genetic factors explain most of why twins and sisters are similar in their MRS, and these genetic factors explain one-quarter to one-half as much breast cancer risk as to the current best genetic risk score. ABSTRACT: Cumulus, Cumulus-percent, Altocumulus, Cirrocumulus, and Cumulus-white are mammogram risk scores (MRSs) for breast cancer based on mammographic density defined in effect by different levels of pixel brightness and adjusted for age and body mass index. We measured these MRS from digitized film mammograms for 593 monozygotic (MZ) and 326 dizygotic (DZ) female twin pairs and 1592 of their sisters. We estimated the correlations in relatives (r) and the proportion of variance due to genetic factors (heritability) using the software FISHER and predicted the familial risk ratio (FRR) associated with each MRS. The ρ estimates ranged from: 0.41 to 0.60 (standard error [SE] 0.02) for MZ pairs, 0.16 to 0.26 (SE 0.05) for DZ pairs, and 0.19 to 0.29 (SE 0.02) for sister pairs (including pairs of a twin and her non-twin sister), respectively. Heritability estimates were 39% to 69% under the classic twin model and 36% to 56% when allowing for shared non-genetic factors specific to MZ pairs. The FRRs were 1.08 to 1.17. These MRSs are substantially familial, due mostly to genetic factors that explain one-quarter to one-half as much of the familial aggregation of breast cancer that is explained by the current best polygenic risk score.