Abstract C167: Understanding the effect of single nucleotide polymorphism rs2292596 on the interaction of aryl hydrocarbon receptor repressor and aryl hydrocarbon receptor nuclear translocator

Abstract

Abstract Lung cancer is the leading cause of cancer death in America. Additionally, the incident rates among Black/African American (B/AA) men and women are significantly higher than those of their white counterparts, despite B/AA’s lower exposure to cigarette smoke (Berg et al, 2010. Journal of Pharmacology and Experimental Therapeutics, Vol. 332, p202). One factor that may increase the risk of lung adenocarcinoma in B/AA individuals is a single nucleotide polymorphism (SNP) found in the aryl hydrocarbon receptor repressor (AHRR) gene. To date, this SNP has been poorly studied, particularly in B/AA individuals. As its name suggests, AHRR represses the detoxification of tobacco smoke induced by aryl hydrocarbon receptor (AHR). Upon exposure to tobacco smoke, AHR enters the nucleus where it dimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT) and binds to xenobiotic response elements (XREs), thereby inducing the genes mediating the detoxification process. Simultaneously, AHRR is turned on as part of a negative feedback loop. AHRR down-regulates the detoxification process by binding to ARNT, forming a negative regulatory complex that binds to XREs. Within the region of AHRR that encodes for the ARNT interaction domain, a single nucleotide polymorphism (SNP) is found in exon 6. SNP rs2292596 encodes a proline or alanine, with 63% of the White subjects having proline while 89% of the B/AA subjects have proline (Single Nucleotide Polymorphism Database, NCBI). As proline is a turn-inducing amino acid, this change, residing in one of the AHRR loops that encircles ARNT, may affect the kinetics of AHRR/ARNT complex association and/or dissociation, thereby potentially affecting the regulatory balance of detoxification. We are currently synthesizing recombinant AHRR protein containing the two different amino acids, along with ARNT. To assess how these changes in the amino acid sequence affect the interaction of AHRR and ARNT, we will measure the association and dissociation rates using a SwitchSense DRX2 instrument. If the SNP affects the kinetics of AHRR/ARNT heterodimer formation, it may affect detoxification and thereby lung cancer risk. If so, in the future the accuracy of lung cancer detection may be improved by increased screening for individuals carrying the risk allele. Furthermore, if the presence of the risk allele implicates a higher risk for lung cancer, this may strengthen lung cancer prevention within the B/AA community. Funding: This research is supported by R21CA290319 from National Institute of Health (NIH)/National Cancer Institute (NCI), the Norris Comprehensive Cancer Center core grant, award number P30CA014089 from the NIH/NCI, and by the Undergraduate Research Associates Program supported by the USC Provost. Citation Format: Shiori Fukutome, Matthew A. Gladstone, Chunli Yan, Diego A. Velarde, Nicholas Mancuso, Ite Offringa. Understanding the effect of single nucleotide polymorphism rs2292596 on the interaction of aryl hydrocarbon receptor repressor and aryl hydrocarbon receptor nuclear translocator [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C167.