Abstract 4581: Interaction between DRD1 and childhood exposure to environmental tobacco smoke modulates lung cancer risk in smokers and never smokers.
Authors: Ryan Brid M. , Robles Ana I. , McClary Andrew C. , Bowman Elise , Vahakangas Kirsi , Olivo-Marston Susan , Yang Ping , Jen Jin , Harris Curtis C. 
Published: August 2014

Abstract
In searching for a role for genetic variation in susceptibility to lung cancer, we postulated that miRNA modulating SNPs within smoking behavior associated genes, such as the nicotinic acetylcholine and dopamine receptor families, could modulate susceptibility to tobacco carcinogens and lung cancer risk. Bioinformatic analyses of these gene families identified 5 SNPs predicted to modulate a miRNA binding site. We assessed these SNPs in the National Cancer Institute-MD case-control study (European American [EA] & African Americans [AA] n=1,438). rs686 in DRD1 (dopamine receptor D1) was associated with a reduced risk of lung cancer after adjustment for age, gender and race (OR 0.63, 95% C.I. 0.47-0.85; P=0.002). As DRD1 mediates dopamine signaling following nicotine exposure, we reasoned that the rs686 variant associates with lung cancer risk via modulation of the nicotine reward pathway. However, adjustment for smoking both in terms of smoking status and pack-years did not significantly modulate the association (OR 0.57, 95% C.I. 0.40-0.81, P=0002). In addition, age at smoking initiation, pack-years of smoking and levels of urinary nicotine metabolites (cotinine and hydroxycotinine) did not vary across rs686 genotypes. Moreover, in an analysis of a never smoking cohort from Mayo Clinic, rs686 was also associated with a reduced risk of lung cancer (OR 0.77, 95% C.I. 0.62-0.97; P=0.027; n=629) (pooled analysis OR 0.61, 95% C.I. 0.47-0.78; P&lt;0.0001; n=2,067). Intriguingly, the association between rs686 and lung cancer risk was only observed in subjects exposed to tobacco smoke during childhood (EA smokers: [OR 0.63, 95% C.I. 0.45-0.88; P=0.007] EA never smokers [OR 0.64, 95% C.I. 0.49-0.85; P=0.002] AA smokers OR 0.31, 95% C.I. 0.11-0.89; P=0.029) (model adjusted as above and for education, adult-second-hand smoke exposure). To further explore a relationship between tobacco and DRD1, we exposed lung cancer cell lines to increasing doses of nicotine and observed a significant increase in DRD1 expression (P=0.009). As DRD1 lies within a CpG island, we are currently testing if this regulation occurs via epigenetic modulation of the DRD1 promoter. While a direct role for DRD1 in lung cancer has not previously been reported, a recent report linked DRD to the cancer stem cell hypothesis. Indeed, our work demonstrates that DRD1 is significantly upregulated in lung cells with cancer stem-like properties. Furthermore, miR-296, predicted to bind to variant rs686 allele, is increased in paired lung cancer tissues (P=0.0003), thus linking a decrease in DRD1 with reduced lung cancer risk. Collectively, our work suggests a novel lung cancer pathway whereby rs686 in DRD1 counteracts the increase in DRD1 imposed by exposure to tobacco smoke in both current and never smokers. Furthermore, it hints at a novel role for the dopamine receptor/signaling pathway in lung carcinogenesis.
Citation Format: Brid M. Ryan, Ana I. Robles, Andrew C. McClary, Elise Bowman, Kirsi Vahakangas, Susan Olivo-Marston, Ping Yang, Jin Jen, Curtis C. Harris. Interaction between DRD1 and childhood exposure to environmental tobacco smoke modulates lung cancer risk in smokers and never smokers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4581. doi:10.1158/1538-7445.AM2013-4581