Functional effect of polymorphisms in 15q25 locus on CHRNA5 mRNA, bulky DNA adducts and TP53 mutations

Abstract

Genome-wide association studies have demonstrated that genetic polymorphisms influence the risk of developing lung cancer. Nicotinic acetylcholine receptor alpha3, alpha5 and beta4 genes (CHRNA3, CHRNA5 and CHRNB4) cluster at the 15q25.1 lung cancer susceptibility locus. We genotyped 310 patients with non-small cell lung cancer and a control group of 348 cancer-free individuals for seven sequence variants located in CHRNA3 and CHRNA5 genes. Two of the polymorphisms (rs3829787 and rs3841324) statistically influenced the risk of developing lung cancer. We found that four of the variants (rs3829787, rs3841324, rs588765 and rs3743073) were associated with differential levels of genetic alterations measured as the levels of hydrophobic DNA adducts in the adjacent histologically normal tissue of the lung cancer patients and as TP53 mutations in their lung tumors. The seven sequence variants formed three haplotypes with a frequency above 5%. The two most frequent haplotypes were associated with the risk of developing lung cancer and with smoking-related DNA alterations. We also found an association between CHRNA5 mRNA levels and the sequence variants or haplotypes. In conclusion, our results showed that several of the polymorphisms and their haplotypes in CHRNA5/CHRNA3 genes may have functional effects on (i) CHRNA5 mRNA levels, (ii) polycyclic aromatic hydrocarbon-DNA adduct levels, (iii) TP53 mutations and (iv) susceptibility to lung cancer. What's new? Genetic polymorphisms on chromosome 15q25.1 have been linked to lung cancer risk. In this study of non-small cell lung cancer (NSCLC) patients, certain variants at 15q25.1 were associated with risk, independent of smoking behavior. The variants were linked to nicotinic acetylcholine receptor CHRNA5 expression, DNA adducts, and mutations in TP53. The results shed light on possible mechanisms of inter-individual differences in lung cancer susceptibility and sensitivity to carcinogens. Copyright © 2012 UICC.