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-telangiec- tasia 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 rs12334811was slightly more pronounced in nonsmokers and in carriers with ataxia-telangi- ectasia 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 protec- tive role in lung cancer development.