ATM sequence variants associate with susceptibility to non-small cell lung cancer.
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.
Yang
Hushan
H
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
Spitz
Margaret R
MR
Stewart
David J
DJ
Lu
Charles
C
Gorlov
Ivan P
IP
Wu
Xifeng
X
D017398:Alternative Splicing / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases