ATM sequence variants associate with susceptibility to non‐small cell lung cancer

Abstract

ATM gene mutations have been implicated in many human cancers. However, the role of ATM polymorphisms in lung carcinogenesis is largely unexplored. We conducted a case‐control analysis of 556 Caucasian non‐small‐cell lung cancer (NSCLC) patients and 556 controls frequency‐matched on age, gender and smoking status. We genotyped 11 single nucleotide polymorphisms of the ATM gene and found that compared with the wild‐type allele‐containing genotypes, the homozygous variant genotypes of ATM08 (rs227060) and ATM10 (rs170548) were associated with elevated NSCLC risk with ORs of 1.55 (95% CI: 1.02–2.35) and 1.51 (0.99–2.31), respectively. ATM haplotypes and diplotypes were inferred using the Expectation‐Maximization algorithm. Haplotype H5 was significantly associated with reduced NSCLC risk in former smokers with an OR of 0.47 (0.25–0.96) compared with the common H1 haplotype. Compared with the H1–H2 diplotype, H2–H2 and H3–H4 diplotypes were associated with increased NSCLC risk with ORs of 1.58 (0.99–2.54) and 2.29 (1.05–5.00), respectively. We then evaluated genotype–phenotype correlation in the control group using the comet assay to determine DNA damage and DNA repair capacity. Compared with individuals with at least 1 wild‐type allele, the homozygous variant carriers of either ATM08 or ATM10 exhibited significantly increased DNA damage as evidenced by a higher mean value of the radiation‐induced olive tail moment (ATM08: 4.86 ± 2.43 vs. 3.79 ± 1.51, p = 0.04; ATM10: 5.14 ± 2.37 vs. 3.79 ± 1.54, p = 0.01). Our study presents the first epidemiologic evidence that ATM genetic variants may affect NSCLC predisposition, and that the risk‐conferring variants might act through down‐regulating the functions of ATM in DNA repair activity upon genetic insults such as ionizing radiation.