Prenatal smoke exposure, DNA methylation and a link between DRD1 and lung cancer

We read with interest the recent work by Richmond et al.¹ where they describe changes in DNA methylation that persist into adulthood among individuals exposed to second-hand smoke in utero. Among the genes affected was DRD1, also known as dopamine receptor, D1. We were struck by this finding as we previously published work describing a gene–environment interaction between a single nucleotide polymorphism (SNP) in DRD1 with risk of lung cancer, specifically among individuals exposed to second-hand smoke during childhood, but not adulthood.² We detected this gene–environment interaction in both ever and never smokers, which is also consistent with the findings of Richmond et al. The SNP of focus in our study was a 3′UTR SNP, rs686. While the methylation probe detected in the study by Richmond et al. lies downstream of DRD1, it is interesting to hypothesize that rs686 could be a tag SNP for a functional locus or methylation expression quantitative trait locus (meQTL) in this gene neighbourhood.

At the time, our observation suggested to us that the gene–environment relationship we described could be mediated by an epigenetic effect — such as methylation — that originated during childhood and persisted into adulthood. Interestingly, while we do not know how DRD1 could contribute to lung-cancer susceptibility, the findings by Richmond et al. now support this possibility. Their data are also strengthened by in vivo studies that similarly describe persistent changes to DRD1 expression and signalling following in utero exposure to cocaine³ and paternal exposure to nicotine.⁴

In his review of the health consequences of involuntary exposure to tobacco smoke, the US Surgeon General concluded that the ‘evidence is sufficient to infer a causal relationship between secondhand smoke exposure and lung cancer among lifetime nonsmokers’, and that ‘this conclusion extends to all secondhand smoke exposure, regardless of location’.⁵ While additional review of the specific relationship between childhood or prenatal exposure to second-hand smoke and lung cancer risk later in life is needed, studies have supported an increased risk of lung cancer in never smokers exposed to second-hand smoke during childhood.⁶ Thus, while detailed molecular analyses still need to be conducted, we posit that prenatal exposure to tobacco smoke causes persistent changes in DRD1 methylation, that these changes contribute to lung-cancer development, and that germline mutations in the DRD1 gene modulate this risk. In light of these studies, and recent evidence suggesting that DRD1 modifies sensitivity to imatinib,⁷ additional research regarding a potential cell-intrinsic mechanistic relationship between DRD1 and lung cancer is warranted.

Conflict of interest: None declared.