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Tagging Single Nucleotide Polymorphisms in Phosphoinositide-3-Kinase–Related Protein Kinase Genes Involved in DNA Damage "Checkpoints" and Lung Cancer Susceptibility

Authors' Affiliations: ¹ Department of Epidemiology and Biostatistics, Cancer Research Center of Nanjing Medical University, Nanjing, China; ² State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University; ³ Shanghai South Gene Technology Co. Ltd.; ⁴ Department of Genetics, Chinese National Human Genome Center at Shanghai; ⁵ Rui Jin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China; and ⁶ Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Hongbing Shen, Department of Epidemiology and Biostatistics, Cancer Research Center of Nanjing Medical University, Nanjing 210029, China. Phone: 86-25-8686-2756; E-mail: hbshen{at}njmu.edu.cn or Wei Huang, Department of Genetics, Chinese National Human Genome Center at Shanghai, Shanghai, China. E-mail: huangwei{at}chgc.sh.cn.

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.