Abstract PO-179: Analysis of long-term exposures to cigarette smoking and female hormones jointly with risk alleles of glucose metabolism in African American hormone receptor positive breast cancer
Authors: Jung Su Yon , Papp Jeanette C. , Sobel Eric M. , Pellegrini Matteo , Yu Herbert 
Published: January 2022

Background: Breast cancer (BC) is the most common cancer diagnosis and cause of death related to cancer in women in the United States and worldwide and more than 80% of new cases and deaths occur in postmenopausal women ages 50 years and older. Whereas African American (AA) women have a lower BC incidence rate than white women (e.g., 126.7 vs. 130.8 cases per 100,000 during 2012–2016), AA women's incidence rates have more rapidly increased than those in white women (0.9% vs. 0.4% per year), contributing to a convergence in BC incidence rates in 2016. BC is also the top leading cause of cancer incidence and mortality in AA women. Glucose intolerance/insulin resistance (IR) is a well-established risk factor for invasive BC development in AA postmenopausal women. While obesity and IR are more prevalent in AA than white women, they are under-represented in genome-wide studies for systemic regulation of IR and the association with BC risk. Methods: By examining 780 genome-wide IR single-nucleotide polymorphisms (SNPs) available in the Women's Health Initiative Database for Genotypes and Phenotypes (WHI dbGaP) SNP Health Association Resource (SHARe), we tested 4,689 AA women for potential causal pathways of genetically determined IR and BC risk in a Mendelian randomization (MR) framework. By incorporating 37 BC-associated lifestyle factors, we further conducted a gene–environment interaction analysis to estimate risk prediction for the most influential genetic and lifestyle factors and evaluated their combined and joint effects on BC risk. Results: Our MR results analyzing 38 index SNPs were mixed. By accounting for variations of individual SNPs in BC risk in the prediction model, we detected 4 fasting glucose–associated SNPs in PCSK1, SPC25, ADCY5, and MTNR1B and 3 lifestyle factors (smoking, oral contraceptive use, and age at menopause) as the most predictive markers for BC risk. Our joint analysis of risk genotypes and lifestyles with smoking revealed a synergistic effect on increased risk of BC, particularly ER/PR+ BC, in a gene–lifestyle dose-dependent manner. The joint effect of smoking on ER/PR+ BC was more profound in women who had long-term exposure to cigarette smoking and a prolonged exposure to female hormones. Conclusion: Our finding may improve the prediction accuracy in BC subtypes and highlight genetically targeted preventive interventions (e.g., smoking cessation) for AA postmenopausal women who carry particular risk genotypes.

Citation Format: Su Yon Jung, Jeanette C. Papp, Eric M. Sobel, Matteo Pellegrini, Herbert Yu. Analysis of long-term exposures to cigarette smoking and female hormones jointly with risk alleles of glucose metabolism in African American hormone receptor positive breast cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-179.