Abstract 3429: Using metabolomics to identify biomarkers mediating the associations of adiposity in childhood and early adulthood with mammographic breast density in premenopausal women

Abstract Introduction: Mammographic breast density (MBD), a strong predictor of breast cancer risk, is highly influenced by body mass index (BMI) in childhood and early adulthood, but the mechanisms elucidating this relationship are undetermined. To our knowledge, no study has explored the mediating role of biomarkers on the relationship between early-life adiposity and MBD. The goal of this study is to discover metabolites that mediate the relationship between BMI at ages 10 and 18 with MBD in premenopausal women. Methods: This study includes premenopausal women who had their screening mammogram at Washington University in St. Louis, MO, and provided a fasting blood sample. Metabolon performed untargeted metabolomic profiling, detecting 1, 074 metabolites. Metabolites missing 300 observations were excluded, leaving 828 metabolites; the other missing values were imputed using the nearest neighbor method. To mitigate batch effect, we normalized the metabolite peak area data using ComBat. Volumetric percent density (VPD) was calculated in 700 women using Volpara software. BMI at age 10 was estimated using the Stunkard pictogram, and BMI at age 18 was calculated from self-reported weight at 18 and height at study initiation. To assess the mediating role of the 828 metabolites, we performed high dimensional mediation analysis using the hima R package adjusting for potential confounders. Missing values in the covariates and BMI measures included in the mediation analysis were imputed using multivariate imputation by chain equations. Associations were considered significant if FDR p-value 0. 1. Results: Four metabolites (glutamate, beta-cryptoxanthin, phytanate, and cortolone glucuronide (1) ) mediated the relationship between BMI at age 10 and VPD; and 2 metabolites (glutamate, beta-cryptoxanthin) mediated the relationship between BMI at age 18 and VPD. Glutamate and beta-cryptoxanthin significantly mediated the relationship between both BMI measures and VPD, but glutamate was the strongest mediator across both time points. Glutamate mediated 6. 7% (FDR p-value=0. 06) and 9. 3% (FDR p-value=0. 008) of the total effect between BMI at age 10 and 18, respectively, on VPD. Beta-cryptoxanthin mediated 4. 1% (FDR p-value=0. 06) and 6. 3% (FDR p-value=0. 04), of the total effect between BMI at age 10 and 18, respectively, on VPD. Additionally, phytanate mediated 2. 6% (FDR p-value=0. 06) and cortolone glucuronide (1) mediated 2. 0% (FDR p-value=0. 07) of the total effect between BMI at age 10 and VPD. Conclusion: Amino acid, lipid, cofactor/vitamin, and xenobiotic metabolites mediated the associations of BMI in early-life and VPD in premenopausal women. This innovative study offers insight into the biological mechanisms underlying the link between early-life adiposity and MBD, which can support future research into breast cancer prevention. Citation Format: Kayla R. Getz, Myung Sik Jeon, Lili Liu, Lei Liu, Chongliang Luo, Jingqin Luo, Adetunji T. Toriola. Using metabolomics to identify biomarkers mediating the associations of adiposity in childhood and early adulthood with mammographic breast density in premenopausal women abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3429.