Radon Exposure, IL-6 Promoter Variants, and Lung Squamous Cell Carcinoma in Former Uranium Miners

Abstract

Background: High radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology observed in former uranium miners. Radon exposure can cause oxidative stress, leading to pulmonary inflammation. Interleukin-6 (IL-6) is a pro-carcinogenic inflammatory cytokine that plays a pivotal role in lung cancer development. Objectives: We assessed whether single nucleotide polymorphisms (SNPs) in the IL6 promoter are associated with lung cancer in former uranium miners with high occupational exposure to radon gas. Methods: Genetic associations were assessed in a case–control study of former uranium miners (242 cases and 336 controls). A replication study was performed using data from the Gene Environment Association Studies (GENEVA) Genome Wide Association Study (GWAS) of Lung Cancer and Smoking. Functional relevance of the SNPs was characterized using in vitro approaches. Results: We found that rs1800797 was associated with squamous cell carcinoma in miners and with a shorter time between the midpoint of the period of substantial exposure and diagnosis among the cases. Furthermore, rs1800797 was also associated with lung cancer among never smokers in the GENEVA dataset. Functional studies identified that the risk allele was associated with increased basal IL-6 mRNA level and greater promoter activity. Furthermore, fibroblasts with the risk allele showed greater induction of IL-6 secretion by hydrogen peroxide or benzo[a]pyrene diolepoxide treatments. Conclusions: An IL6 promoter variant was associated with lung cancer in uranium miners and never smokers in two external study populations. The associations are strongly supported by the functional relevance that the IL6 promoter SNP affects basal expression and carcinogen-induced IL-6 secretion. Citation: Leng S, Thomas CL, Snider AM, Picchi MA, Chen W, Willis DG, Carr TG, Krzeminski J, Desai D, Shantu A, Lin Y, Jacobson MR, Belinsky SA. 2016. Radon exposure, IL-6 promoter variants, and lung squamous cell carcinoma in former uranium miners. Environ Health Perspect 124:445–451; http://dx.doi.org/10.1289/ehp.1409437

Association of polymorphism <i>TP53</i> Arg72Pro with radon-induced lung cancer in the Kazakh population

“…Yngveson et al (1999) have shown that residential exposure to radon seems to contribute to a higher mutation prevalence of the TP53 gene in lung tumors, especially among nonsmokers. There are only few studies on radon exposure and gene poly morphisms (Bonner et al, 2006;RuanoRavina et al, 2014;Leng et al, 2016). Two of them provided evidence for an interaction between members of the glutathione Stransferase family GSTT1 (RuanoRavina et al, 2014) and GSTM1 (Bon ner et al, 2006;RuanoRavina et al, 2014) and radon in lung cancer risk.…”

“…Two of them provided evidence for an interaction between members of the glutathione Stransferase family GSTT1 (RuanoRavina et al, 2014) and GSTM1 (Bon ner et al, 2006;RuanoRavina et al, 2014) and radon in lung cancer risk. The association between IL-6 promoter SNPs and squamous cell carcinoma was studied in uranium miners (Leng et al, 2016). Choi et al (2018) identified that CHD4 rs74790047, TSC2 rs2121870, and AR rs66766408 are found to be common exonic mutations in both lung cancer patients and normal individuals exposed to radon indoors.…”

Circular RNA profiles in mouse lung tissue induced by radon

“…Genome damage, such as genome instability, was found in peripheral blood lymphocytes of lung cancer patients living in a region with high air pollution and increased background radon levels [ 5 , 20 ]. Moreover, IL-6 promoter variant was associated with lung cancer in uranium miners [ 21 ]. Reports show that caspase-3 is involved in cell apoptosis [ 22 , 23 ].…”

Concerted Uranium Research in Europe (CURE): toward a collaborative project integrating dosimetry, epidemiology and radiobiology to study the effects of occupational uranium exposure

“…It might be informative to also conduct pilot studies in areas outside Western Europe, where workers have had higher levels of uranium exposure in recent years, but where more stringent standards (important to the conduct of ethical research) are being, or are about to be, implemented. As part of CURE, contacts have been established with research teams involved in research projects on uranium effects outside Europe: USA , Leng et al 2016, Kazakhstan (Kazymbet et al 2012) and Russia (Takhauov et al 2015). Conducting pilot molecular epidemiological studies in these countries would provide a wider, scientifically pertinent, perspective.…”