Is Mammographic Breast Density an Endophenotype for Breast Cancer?

SIMPLE SUMMARY: Candidate endophenotypes should be systematically assessed against five criteria: (i) the endophenotype is associated with disease in the population; (ii) the endophenotype is heritable; (iii) within families, endophenotype and disease co-segregate; (iv) the endophenotype found in affected family members is found in non-affected family members at a higher rate than in the general population and (v) the endophenotype is primarily state independent (manifests in an individual whether or not disease is active). This study assesses the suitability of mammographic breast density as an endophenotype for breast cancer. Formally establishing a trait as a disease endophenotype confirms that the trait and endophenotype share a biological basis, thereby enabling genetic dissection of an endophenotype to inform disease risk. As breast density can be measured for any woman who has had a mammogram, studies investigating the genetic architecture of breast density could identify breast cancer risk variants that act through effects on this trait. ABSTRACT: Mammographic breast density (MBD) is a strong and highly heritable predictor of breast cancer risk and a biomarker for the disease. This study systematically assesses MBD as an endophenotype for breast cancer—a quantitative trait that is heritable and genetically correlated with disease risk. Using data from the family-based kConFab Study and the 1994/1995 cross-sectional Busselton Health Study, participants were divided into three status groups—cases, relatives of cases and controls. Participant’s mammograms were used to measure absolute dense area (DA) and percentage dense area (PDA). To address each endophenotype criterion, linear mixed models and heritability analysis were conducted. Both measures of MBD were significantly associated with breast cancer risk in two independent samples. These measures were also highly heritable. Meta-analyses of both studies showed that MBD measures were higher in cases compared to relatives (β = 0.48, 95% CI = 0.10, 0.86 and β = 0.41, 95% CI = 0.06, 0.78 for DA and PDA, respectively) and in relatives compared to controls (β = 0.16, 95% CI = −0.24, 0.56 and β = 0.16, 95% CI = −0.21, 0.53 for DA and PDA, respectively). This study formally demonstrates, for the first time, that MBD is an endophenotype for breast cancer.