Genetic Susceptibility to Lung Squamous Cell Carcinoma: New Insights on 9q33.2 Variants and Tobacco Smoking

Genome-wide association studies (GWAS) have identified over 60 susceptibility loci for lung cancer, yet the biological mechanisms underlying these associations remain largely unknown, particularly for lung squamous cell carcinoma (LUSC). Here, we integrated data from 3890 LUSC cases and 13328 controls of Chinese descent, and performed a conditional analysis to explore independent genetic variants and analyzed the interaction between the genetic variants and smoking. Our study was the first to identify a specific association between genetic variants in the 9q33.2 region and increased risk of LUSC in smokers. After adjusting for the tag SNP rs4573350 in 9q33.2, no additional significant genetic variants were found. However, significant additive (RERI=1.66, 95%CI: 1.17-2.22, AP=0.26, 95%CI: 0.19-0.33) and multiple interactions (OR=1.30, 95%CI: 1.08-1.56, P=5.40×10-3) were observed between rs4573350 and smoking. Compared to nonsmokers with the CC genotype, smokers with the CT/TT genotype showed an increased risk of 6.29-fold (95%CI: 5.46-7.23, P=2.00×10-16). Functional annotation identified rs4573350 as the strongest functional variant within the linkage disequilibrium block. Biological experiments confirmed that the combined exposure to the T allele of rs4573350 and cigarette smoke extract promotes the expression of the ZBTB26 by modulating the binding ability of the transcription factor FOXA1. Furthermore, ZBTB26 was found to regulate tumorigenesis of LUSC both in vitro and in vivo by affecting the expression of PCNA, which is involved in cell cycle and promotes tumorigenesis of LUSC.