Abstract PO-180: Synergistic interplay between genetic characteristics of glucose homeostasis and long-term exposure to cigarette smoking in development of African American colorectal cancer

Abstract

Abstract Background: Colorectal cancer (CRC) is the leading cause of cancer diagnosis and death in women in the United States and other westernized countries and approximately 90% of new cases and deaths occur in women 50 years old and older. African American (AA) women have the highest CRC incidence and mortality rates among all races/ethnic female groups. Also, CRC is the third most common cancer diagnosis and cause of cancer deaths in AA women. Insulin resistance (IR) or glucose intolerance is a critical biologic mechanism for the development of CRC owing to obesity in postmenopausal women. Whereas IR and excessive adiposity are more prevalent in AA women than in white women, AA women are under-represented in genome-wide studies for systemic regulation of IR and the association with CRC risk. Methods: Having examined 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) among 4,692 AA women, we tested for a causal inference between genetically elevated IR and CRC risk in a Mendelian randomization (MR) framework. Further, by incorporating 35 CRC-associated lifestyle factors, we established a prediction model on the basis of gene–environment interactions to generate risk profiles for CRC with the most influential genetic and lifestyle factors and eventually estimated their combined and joint effects on CRC risk. Results: In the pooled MR analysis, the genetically elevated IR was associated with 9 times increased risk for CRC. By addressing the variation of individual SNPs in CRC risk in the prediction model, we detected 4 fasting glucose–specific SNPs in GCK, PCSK1, and MTNR1B and 4 lifestyles, including smoking, aging, prolonged lifetime exposure to endogenous estrogen, and high fat intake, as the most predictive markers for CRC risk. Our joint test for those risk genotypes and lifestyles with smoking revealed the synergistically increased CRC risk, more substantially in women with longer-term exposure to cigarette smoking. Conclusion: Our findings may improve CRC prediction ability among medically under-represented AA women and highlight genetically informed preventive interventions (e.g., smoking cessation; CRC screening to longer-term smokers) for those women at high risk with risk genotypes and behavioral patterns. Citation Format: Su Yon Jung. Synergistic interplay between genetic characteristics of glucose homeostasis and long-term exposure to cigarette smoking in development of African American colorectal 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-180.