WASHINGTON (GenomeWeb News) – A SNP in a dopamine receptor gene appears to interact with childhood exposure to secondhand smoke to modulate lung cancer risk, reported Bríd Ryan, a research fellow at the National Cancer Institute, during the American Association for Cancer Research annual meeting yesterday.
Ryan and her colleagues hypothesized that SNPs found within genes associated with smoking behavior like DRD1, which is associated with nicotine addiction, could affect susceptibility to tobacco-related carcinogens and cancer risk.
The session during which Ryan presented this report showcased how researchers are using genome-wide association studies and, increasingly, other genomics techniques to tease out how environmental and genetic factors influence disease risk, especially in cancer.
Drawing on the NCI-MD case-control study, Ryan and her colleagues examined both lifestyle and genotype data, finding a link between the SNP rs686, childhood exposure to tobacco smoke, and a decreased risk of developing lung cancer. The effect was not associated with exposure to secondhand smoke in adulthood, but once established in childhood, "that pattern carried throughout adulthood," Ryan said.
Ryan and her colleagues conducted a bioinformatic analysis and first found five SNPs in gene families associated with smoking behaviors. One of those SNPs, rs686, was associated with a reduced risk for lung cancer within the NCI-MD case-control study cohort, which consisted of 1,483 European Americans and African Americans, leading the researchers to suspect that rs686 modulated risk by working through the nicotine reward pathway.
However, when they broke apart the cohort by race, the effect was limited to people of European descent. Controlling for smoking status and pack-years did not alter the association, and neither did adding in age at smoking initiation. In addition, through a metabolomic study, they found no difference between nicotine metabolite levels and genotype, Ryan said.
The effect, though, of rs686 being associated with decreased lung cancer risk was also seen in a cohort from the Mayo Clinic of people who have never smoked. Here, though, Ryan and her colleagues noted that the association was only seen in people who were exposed to secondhand smoke as a child and not those exposed during adulthood. "[The SNP] rs686 is associated with decreased lung cancer risk in individuals exposed to secondhand smoke during childhood," Ryan said.
The Mayo cohort included nearly 3,000 people, both of African and European descent, and the effect held in both groups of people, she noted. Further, the SNP appeared to decrease the risk of developing both adenoma of the lung and squamous cell lung cancer.
Ryan also reported that lung cancer cell lines exposed to increasing levels of nicotine showed increased DRD1 expression. In addition, DRD-positive and DRD-negative cells have differential tumorigenicity, she added.
While Ryan and her colleagues are examining how DRD1 has this modulating effect, they suspect it might be through epigenetic regulation of the DRD1 promoter. Nicotine exposure, she said, could demethylate the DRD gene in childhood and that change could be then carried into adulthood.