Abstract PO4-08-06: Causal Relationships and Familial Aggregation of Mammogram Risk Scores: Insights from Breast Cancer in Twins and Families
Authors: Ye Zhoufeng , Li Shuai , Dite Gill , Nguyen Tuong , MacInnis Robert , Hopper John 
Published: May 2024

Abstract
Background: Mammogram risk scores based on texture and density, determined by brightness thresholds, are associated with breast cancer risk differently and could reveal distinct information about breast cancer risk. This study aimed to investigate the causal relationships between these intercorrelated risk scores and the familial aggregation of a texture-based mammogram measure, shedding light on the relevance to breast cancer aetiology.
Methods: We analysed data from the Australian Mammographic Density Twins and Sisters Study, including 3195 breast-cancer-free women from 1519 families. The dataset comprised 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1599 sisters. The average age at mammography for sister pairs ranged from 40 to 70 years. Mammogram risk scores based on texture (named Cirrus) and three density-defined areas (light, bright, and brightest) that were spatially independent were generated. The Inference about Causation from Examination of Familial Confounding (ICE FALCON) method was employed for causal inference. Familial aggregation and the variance of Cirrus were assessed as a function of age using a multivariate normal model for pedigree analysis. The classic twin model was employed but allowing for varying shared environmental effects among different sister pairs. The single-nucleotide polymorphism (SNP)-based heritability was estimated using genetic variants from both closely and distantly related individuals. Model fits were compared using likelihood ratio tests and the Akaike Information Criterion.
Results: Causal analysis using ICE FALCON revealed significant positive causal effects, with Cirrus, light areas, and bright areas influencing the brightest areas (accounting for 34%, 55%, and 85% of the associations, respectively). Similarly, light areas and bright areas demonstrated causal effects on Cirrus (accounting for 37% and 28% of the associations, respectively). No age-related differences in familial correlations or Cirrus variance were found for women aged 40 to 70 years. Familial correlations were estimated at 0.51 (0.03) for MZ pairs and 0.16 (0.03) for combined DZ and non-twin sister pairs, with no significant difference between DZ and non-twin sister pairs (P=0.3). Additive genetic effects accounted for up to 32% (5%) of the variance, consistent with SNP-based heritability estimates of 36% (12%). MZ-specific environmental effects contributed to at least 20% (3%), while shared environmental effects for DZ and non-twin sibling pairs accounted for less than 40% of that for MZ pairs.
Conclusion: In a mammogram, the lighter (less dense) areas causally influence the brightest (highly dense) areas, including through textural features. These causal relationships provide insights into the relative importance of different mammogram features in breast cancer aetiology. For example, the brightest areas are more aetiologically important for screen-detected breast cancer, while the light areas are more aetiologically important for interval breast cancer. Additionally, specific textural features capture aetiologically independent breast cancer risk information from dense areas. We also confirm the partial heritability of Cirrus, the texture-based mammogram measure, substantially influenced by environmental factors (familial and non-familial). As well as genetic factors, Cirrus could be determined by factors operating at times of life when MZ pairs share their environments to a greater extent than do DZ and non-twin sisters, starting in utero and prior to adulthood, and remaining constant thereafter. These insights from twin and family data enhance our understanding of mammogram risk scores and their implications for breast cancer risk assessment.
Citation Format: Zhoufeng Ye, Shuai Li, Gill Dite, Tuong Nguyen, Robert MacInnis, John Hopper. Causal Relationships and Familial Aggregation of Mammogram Risk Scores: Insights from Breast Cancer in Twins and Families [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-08-06.