Gene–radon interaction effects on lung cancer risk: validation of susceptibility loci using archived DNA from German Uranium miners

Background Radon exposure increases lung cancer risk, shown in studies on indoor exposure (low exposure) and uranium miners (high exposure). Genome-wide and candidate gene studies have identified DNA variants that interact with occupational radon to modify lung cancer risk. Method Highly fragmented DNA samples of 611 individuals were genotyped using next-generation sequencing. DNA variant associations could be assessed in 526 out of 611 WISMUT uranium miners with lung cancer. The relative risk of lung cancer per allele (marginal effect) as well as its dependence on radon exposure (gene-environment (GxE) interaction) could be estimated from the enrichment of one allele compared to the distribution of genotypes expected under the HWE assumption (Hardy-Weinberg equilibrium). Exposure to gamma radiation, long-lived radionuclides, fine dust, silicate dust and arsenic was considered in the same way. Results For markers from six ( UBE2U , CDKN2A , SIRT1 , NAV2 , ST8SIA2 , TP53 ) of the 10 genes examined, a significant modification of the genetic relative risk for lung cancer due to mining-specific radon exposure [in WLM] was observed. Conclusion Radon exposure may be the main cause of some of the observed GxE interactions involving UBE2U , CDKN2A and SIRT1 , but it may not be the only one. This conclusion is supported by the function of these genes, as based on relevant literature. For another marker of the gene SOX5 , a GxE interaction can presumably be attributed to exposure to arsenic. For the remaining genes, no single environmental factor (radon, dust or arsenic) can unambiguously be identified as sole cause of the GxE interaction. Clinical trial number Not applicable.