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Clinical Cancer Research 14, 2887, May 1, 2008. doi: 10.1158/1078-0432.CCR-07-1822
© 2008 American Association for Cancer Research
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Cancer Prevention and Susceptibility

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

Zhibin Hu1, Hongliang Liu2, Haifeng Wang3, Ruifen Miao1, Weiwei Sun3, Guangfu Jin1, Ying Wang4, Hongxia Ma1, Li Jin2, Qingyi Wei6, Daru Lu2, Wei Huang4,5 and Hongbing Shen1

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.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
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.

Maintenance of genome stability is essential for avoiding the passage to neoplasia. DNA lesions that are not properly repaired before cell division can be mutagenic, resulting in mutations and the formation of a precancerous cell (1, 2). A wealth of information has been accumulated on DNA repair mechanisms over the past 50 years. Genetic defects disturbing these mechanisms can cause inherited syndromes that are characterized by hypersensitivity to specific DNA-damaging agents and predisposition to cancer (3). Although the repair of different types of DNA lesion relies on different sets of proteins, the various forms of DNA damage nevertheless trigger common response signals, such as DNA damage "checkpoints" (4, 5).

Before detecting a specific type of DNA lesions, the cell must sense very low levels of DNA damage in the genome. The rapidity and potency of this DNA damage response demand very sensitive signal transduction cascades, initiated by the sensor proteins of the phosphoinositide-3-kinase–related protein kinase (PIKK) family, including ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia and Rad3-related (ATR), and DNA-dependent protein kinase catalytic subunit (DNA-PKcs; refs. 4, 6). ATM and DNA-PKcs respond mainly to DNA double-strand breaks, whereas ATR is activated by ssDNA and stalled DNA replication forks (7). Recently, Falck et al. (8) identified related, conserved COOH-terminal motifs in human NBS1, ATRIP, and Ku80 proteins that are required for their interaction with ATM, ATR, and DNA-PKcs of PIKKs, respectively, and provided direct evidence that PIKK recruitment is required for PIKK-dependent DNA damage signaling.

Disruption of ATR causes cell lethality (9), whereas ATM defects give rise to ataxia-telangiectasia, a debilitating human neurodegenerative and cancer predisposition disease (9, 10). Bartkova et al. reported that in clinical specimens from different stages of human tumors of the lung, urinary bladder, breast, colon, and also early precursor lesions, markers of an activated DNA damage response were commonly expressed, including phosphorylated ATM, H2AX, and p53. This PIKK-regulated DNA damage response network can delay or prevent cancer early in tumorigenesis before genomic instability and malignant conversion (11). Genetic variants in ATM/ATR have been extensively studied in multiple cancers, including lung cancer (12–14). Although DNA-PKcs has a role that partly overlaps with that of ATM, polymorphisms in DNA-PKcs have been rarely investigated in cancer susceptibility (15, 16). Here, we assessed the association between common variants across the DNA-PKcs gene region and lung cancer susceptibility. In addition, we also included two representative single nucleotide polymorphisms (SNP) in ATM/ATR to elucidate their possible gene-gene interactions in the etiology of lung cancer.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Study populations. The study population and subject characteristics were described elsewhere (17). In brief, this hospital-based case-control study included 500 histopathologically confirmed incident lung cancer patients and 517 cancer-free controls, frequency-matched to the cases on age, sex, and residential areas. Pack-years smoked [(cigarettes per day ÷ 20) x years smoked] were calculated to indicate the cumulative smoking dose. Family history of cancer was defined as any self-reported cancer in first-degree relatives (parents, siblings, or children). The study was approved by the institutional review boards of Nanjing Medical University.

SNP selection and genotyping assays. Human DNA-PKcs gene had 556 SNPs in National Center for Biotechnology Information dbSNP database (build 127), 43 of which were common (i.e., minor allele frequency ≥ 0.05) among Asian or Chinese populations. The HapMap public SNP database (HapMap Data Rel#22/PhaseII Apr07, dbSNP build 126, Chr8:48,847,222..49,036,295, 1,000 bp upstream and downstream DNA-PKcs 5' and 3' untranslated region) provided a dense coverage across DNA-PKcs with 225 SNPs genotyped, including 31 common SNPs among Chinese. We then selected 10 tagging SNPs (tSNP) using a pairwise Tagger method with a r2 cutoff value of 0.8 to capture all the common SNPs in DNA-PKcs and the mean of r2 is 0.975. For ATM and ATR, we chose only one representative tSNP that captures most SNPs in each gene based on the HapMap database (ATM: rs228591 and ATR: rs6782400). Because ATM rs609429 and rs664143 are positively associated with lung cancer risk in two reported studies (12, 13), we first genotyped ATM rs228591, ATM rs609429, and ATM rs664143 in a pilot study with 96 controls and found that rs228591 was in highly linkage disequilibrium with both rs609429 (D' = 0.973; r2 = 0.923) and rs664143 (D' = 1.000; r2 = 0.974). For the potentially functional SNP in ATR (rs2227928, T211M) as previously reported (14), we also found that ATR rs2227928 was in complete linkage disequilibrium with ATR rs6782400 (HapMap Data Rel#22/PhaseII Apr07). Therefore, for these 14 SNPs, we continued the genotyping for 10 tSNPs of DNA-PKcs, 1 tSNP of ATM (rs228591), and 1 tSNP of ATR (rs6782400) that were included in the final analysis.

Ten of the 14 SNPs were genotyped by using the Illumina SNP genotyping BeadLab platform at Chinese National Human Genome Center at Shanghai and the rest 4 SNPs (rs4873772, rs12334811, rs609429, and rs664143) were genotyped by using the PCR-RFLP assay at Cancer Research Center of Nanjing Medical University. The information on the PCR-RFLP assays is presented in Table 1 and the information on the Illumina assay conditions is available on request. For the Illumina high-throughput genotyping platform, routine quality control method was used as the Chinese National Human Genome Center at Shanghai used in their work for the international HapMap project (i.e., one blank well and three repeated samples). The repeated samples were randomly chosen from each 96-well assay plate so that we could find if contamination occurred and judge the clusters of genotype. The assay products were hybridized to high-density, bead-based microarrays and imaged on the Sherlock scanner. The "GenCall" software runs clustering and calling algorithms with the genotyping result output. We used the "GenCall score" as calling criteria, and the loci with >0.25 were reserved. For the PCR-RFLP assay, genotyping was done without knowing the subjects' case and control status, and almost the same number of cases and controls was assayed in each 96-well PCR plate with a positive control of a DNA sample with known heterozygous genotype. Ten percent of the samples were randomly selected to do the repeated assays. Furthermore, 96 samples of the SNP rs7003908 were randomly selected to verify the results by Illumina BeadLab platform by using the PCR-RFLP assay, and the results were 100% concordant.


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  		Table 1. Primary information on the PCR-RFLP assay of five DNA-PKcs and ATM variants

 
Statistical analysis. The Hardy-Weinberg equilibrium test was done for each genotyped SNP among controls. Differences in select demographic variables, smoking status, pack-years smoked, and frequencies of the PIKK genotypes between the cases and controls were evaluated by using the {chi}2 test. The associations between PIKK variants and lung cancer risk were estimated by computing the odds ratios (OR) and 95% confidence intervals (95% CI) from both univariate and multivariate logistic regression analyses. The association between combined DNA-PKcs (rs12334811 and rs8178085) genotypes and lung cancer risk was also evaluated by stratification analyses by age, sex, smoking status, histologic classifications, and ATM/ATR genetic variants. The potential gene-environment interaction was evaluated by logistic regression analysis and tested by comparing the changes in deviance (–2 log likelihood) between the models of main effects with or without the interaction term. All the statistical analyses were done with Statistical Analysis System software (v.9.1.3; SAS Institute).


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
The distribution of selected characteristics between lung cancer patients and controls was previously described (17). Overall, our frequency matching on age and sex was adequate (P = 0.661 for age and P = 1.000 for gender). Smoking and family history of cancer in first-degree relatives were significant risk factors for lung cancer. Of the 500 cancer patients, 229 were adenocarcinoma, 141 were squamous cell carcinoma, 34 were small cell carcinoma, and 96 were large cell, mixed cell, or undifferentiated carcinomas.

The position and minor allele frequency among Chinese of the 14 SNPs in HapMap database were presented in Table 2 . All SNPs were in Hardy-Weinberg equilibrium among controls, except for rs12334811, rs8178095, and rs7003908. Single locus analyses revealed that the heterozygotes or variant homozygotes of several SNPs in DNA-PKcs were associated with a significantly decreased risk of lung cancer (OR, 0.28; 95% CI, 0.09-0.89 and OR, 0.33; 95% CI, 0.13-0.84 for rs12334811 and rs4873737 variant homozygotes, respectively; OR, 0.65; 95% CI, 0.44-0.95 and OR, 0.76; 95% CI, 0.59-1.00 for rs8178085 and rs7003908 heterozygotes, respectively) compared with their wild-type homozygotes, respectively, and a dose response of the allele effect was found for the rs8178085 SNP with a P trend value of 0.010 and approaching for the rs12334811 SNP with a P trend value of 0.067 (Table 3 ).


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  		Table 2. Primary information for 14 genotyped SNPs of PIKKs

 

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  		Table 3. Main effects of PIKK SNPs on lung cancer risk

 
We then combined the two tSNPs (rs8178085 and rs12334811) with approaching dose-dependent effect on lung cancer predisposition. We found that 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 OR, 0.53; 95% CI, 0.35-0.80; Table 4 ). Moreover, the decreased risk associated with the combined genotypes of rs8178085 and rs12334811 was slightly more pronounced in nonsmokers (OR, 0.45; 95% CI, 0.23-0.88) and in carriers with ATM rs228591 variant allele (OR, 0.42; 95% CI, 0.24-0.72) or ATR rs6782400 wild-type homozygous genotype (OR, 0.42; 95% CI, 0.18-0.95). However, no evidence of gene-gene and/or gene-environment interactions was found (Table 4).


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  		Table 4. Stratification and interaction analyses of combined DNA-PKcs rs12334811 and rs8178085 genotypes and lung cancer risk

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this hospital-based case-control study, we investigated the association of tSNPs of PIKK genes and the susceptibility to lung cancer in a Chinese population. Our results provided evidence, for the first time, that tSNPs in DNA-PKcs may play a protective role in lung cancer development. However, no main effect was found for either ATM rs228591 or ATR rs6782400 on lung cancer risk.

Recruitment of DNA damage-associated PIKKs to DNA lesions is thought to be a principal step in their activation and function in checkpoint signaling and DNA repair (7). An early event in the cascade of the activated DNA damage response is the massive phosphorylation of a histone protein variant called H2AX, which could be ATM dependent following DNA double-strand break induction (18) and ATR dependent following replication stress (19). Phosphorylated H2AX (called {gamma}-H2AX) is thought to be essential for further recruitment of repair factors, such as the MRN complex, 53BP1, MDC1, RAD51, and BRCA1, serving as an important step that determines subsequent events in the signal transduction pathway (20–23). Recently, Stiff et al. (24) reported that DNA-PKcs plays a redundant, overlapping role with ATM in contributing to H2AX phosphorylation. Cells defective in DNA-PKcs components are hypersensitive to killing by ionizing radiation due to an inability to repair DNA double-strand breaks effectively. Moreover, cells defective in DNA-PKcs are also unable to do V(D)J recombination, a site-specific recombination process that takes place in developing B and T lymphocytes (25), which may implicate another role in cancer surveillance through DNA-PKcs.

To date, few molecular epidemiologic studies on the DNA-PKcs genotypes and cancer susceptibility have been reported (15, 16). Fu et al. reported that DNA-PKcs rs2213178 did not contribute to breast cancer risk in a case-control study of 254 breast cancer patients and 379 controls in a Chinese population (15). Recently, Liu et al. (16) genotyped nine tSNPs in a case-control study of 771 glioma patients and 752 healthy controls and found no main effects of DNA-PKcs variants on glioma susceptibility. In the current study, several SNPs in DNA-PKcs showed protective effect on lung cancer risk and most of the positive loci showed a departure from Hardy-Weinberg equilibrium in controls, which may result from misclassification of the genotypes, selection bias of the population, or true effect on disease phenotype and evolution. For one of the genotyped SNPs, DNA-PKcs rs7003908, which did not agree with Hardy-Weinberg equilibrium in controls, two different genotyping methods were applied and the results were 100% consistent. For DNA-PKcs rs12334811, we genotyped manually by the PCR-RFLP assay. Because the wild-type allele had the restriction enzyme site, we regenotyped all the samples with variant alleles to see if the results were affected by enzyme quantity or quality and we also got 100% concordance. Therefore, misclassification of genotypes should not affect our result, if any. Furthermore, genotypes in controls in HapMap database for DNA-PKcs rs12334811 also departed from Hardy-Weinberg equilibrium, suggesting that our result was not simply a chance finding. However, our results need to be validated in larger studies, and how and whether evolution process affected allele frequency of DNA-PKcs variants among different ethnic populations need further investigation.

For ATM/ATR SNPs and lung cancer susceptibility, Zienolddiny et al. (14) reported that ATR Thr211Met (rs2227928) may contribute to lung cancer risk with a case-control study (343 cases and 413 controls) of Norwegian origin; Landi et al. (12) reported that variant homozygote of ATM rs609429 was associated with a decreased lung cancer risk in a case-control study of 299 young-onset lung cancer cases and 317 controls of Eastern European; and Kim et al. (13) showed that ATM rs664143 may alter lung cancer risk in a case-control study of 616 cases and 616 controls of Korean. All these SNPs could be captured by our genotyped ATM/ATR SNPs (see SNP selection). However, we did not find the significant main effect of the two tSNPs of ATM/ATR on lung cancer risk. The discrepancies between the reported studies and our current study may be due to potential selection bias, different ethnic background and environmental exposures, and/or small sample size with limited statistical power.

In conclusion, this is the first study that analyzed genetic variants in PIKK genes and lung cancer susceptibility. The findings need to be validated by larger studies with diverse populations.


   Footnotes
 
Grant support: National Outstanding Youth Science Foundation of China 30425001 (H. Shen), China National Key Basic Research Program Grants 2002CB512902 (D. Lu and H. Shen) and 2002BA711A10 and 2004CB518605 (W. Huang), and National "211" Environmental Genomics Grant (D. Lu).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Z. Hu and H. Liu contributed equally to this work.

Received 7/24/07; revised 10/31/07; accepted 12/26/07.


   References
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 Materials and Methods
 Results
 Discussion
 References
 

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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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