Tagging single nucleotide polymorphisms in phosphoinositide-3-kinase-related protein kinase genes involved in DNA damage "checkpoints" and lung cancer susceptibility.
PURPOSE: DNA damage checkpoints are initiated by its sensor proteins of the phosphoinositide-3-kinase-related protein kinase family, including ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We hypothesized that polymorphisms in these genes may alter the regulation of DNA repair and the risk of lung cancer. EXPERIMENTAL DESIGN: We genotyped 12 tagging single nucleotide polymorphisms (tSNP) in these three phosphoinositide-3-kinase-related protein kinase genes in 500 incident lung cancer cases and 517 controls in a Chinese population by using the Illumina SNP genotyping BeadLab platform. RESULTS: Single locus analyses revealed that some of the heterozygotes or variant homozygotes of DNA-PKcs tSNPs were associated with decreased risks of lung cancer compared with their wild-type homozygotes. In the combined analyses of two tSNPs (rs8178085 and rs12334811) with approaching dose-dependent effect on lung cancer predisposition, subjects carrying two to four risk genotypes were associated with a 43% decreased lung cancer risk compared with subjects carrying zero to one risk genotypes (adjusted odds ratio, 0.53; 95% confidence interval, 0.35-0.80). Moreover, the decreased risk associated with the combined genotypes of rs8178085 and rs12334811 was slightly more pronounced in nonsmokers and in carriers with ataxia-telangiectasia mutated rs228591 variant allele or ataxia-telangiectasia and Rad3-related rs6782400 wild-type homozygous genotype. CONCLUSION: These results indicate, for the first time, that tSNPs in DNA-PKcs may play a protective role in lung cancer development.
Hu, Z; Liu, H; Wang, H; Miao, R; Sun, W; Jin, G; Wang, Y; Ma, H; Jin, L; Wei, Q; Lu, D; Huang, W; Shen, H
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