Joint Effects of Co-Exposure to Polycyclic Aromatic Hydrocarbons Exposure and Smoking with XPC Polymorphisms on Damage in Exon 2 of KRAS Gene Among Young Coke-Oven Workers

Abstract Background Genetic polymorphisms may contribute to variable individual susceptibility to DNA damage induced by co-exposure to polycyclic aromatic hydrocarbons (PAHs) and smoking. Here, we evaluate the joint effects of co-exposure to PAHs and smoking with polymorphisms in XPC, alone or combined, on damage in exons. Methods 288 healthy male coke-oven workers were enrolled into this study, urinary 1-hydroxypyrene (1-OH-pyr), as an indirect and sensitive indicator of PAHs exposure, was detected. Base modification in exons of KRAS and BRAF gene, and polymorphisms of XPC were determined by real-time PCR in plasma samples. Results We observed urinary 1-OH-pyr was positively related to damage index of exon 2 of KRAS gene (KRAS-2) and damage index of exon 15 of BRAF gene (BRAF-15) (both p < 0.001), and KRAS-2 and BRAF-15 were both significantly associated with increased urinary 1-OH-pyr (both p trend < 0.001). A stratified analysis found that urinary 1-OH-pyr was found to be significantly associated with KRAS-2 in both smokers (p < 0.001) and nonsmokers (p < 0.05), while urinary 1-OH-pyr was significantly associated with BRAF-15 only in smokers (p < 0.001). Additionally, rs2228001 in the XPC gene was positively associated with KRAS-2 (p trend < 0.001), and the high levels of 1-OH-pyr were linearly associated with KRAS-2 only in rs2228001 GG+GT genotype carriers (p < 0.001); However, another SNP rs3731055 in the XPC gene was associated with lower KRAS-2 (p trend = 0.006), and the high levels of 1-OH-pyr were linearly associated with KRAS-2 only in rs3731055 GG genotype carriers (p < 0.001). Moreover, KRAS-2 significantly increased with high levels of 1-OH-pyr exposure, smoking, rs2228001 G-allele, and rs3731055 GG homozygote genotype, and we found the most severe KRAS-2 among subjects carrying all 4 of the above risk factors. Conclusions Our findings indicated that the co-exposure effect of PAHs and cigarette smoking could increase the risk of damage in exon 2 of KRAS by a mechanism partly involving XPC polymorphisms.