Association Of Genetic Polymorphisms Of DNA Repair Genes With Lung Cancer Risk

Lung cancer is the leading cause of death in all kinds of cancers. All kinds of damages such as from exposure to exogenous environmental xenobiotics and to endogenous damage may result in an early event in Carcinogenesis. Most of DNA repair genes have single nucleotide polymorphisms. It is necessary to evaluate the relationship between the polymorphisms of DNA repair gene and the susceptibility of lung cancer. In this study, to comprehensively examined the roles of the polymorphisms of the key gene XRCC1 in the BER pathway and the roles of the polymorphisms of three core genes XPA, XPC and XPD in the NER pathway in the development of lung cancer. At first, we performed a case-control study of 251 lung cancer cases and 301 age and sex frequency-matched healthy controls. We selected 13 tagSNPs on the base of the data from Han Chinese in Beijing provided by the HapMap database and the linkage disequilibrium(LD) analysis. The tagSNPs was genotyped using Taqman platform. We successfully got genotype data of 11 tagSNPs and examined the single, joint and interactional effects between these polymorphisms and smoking on lung cancer susceptibility. We also inferred the haplotype of above four genes and evaluated the association between these haplotypes and lung cancer risk. Secondly, a variety of studies have been performed to investigate the association between the potential functional SNPs of NER genes and lung cancer risk. However, the investigations did not provide consistent results. We conduct a meta-analysis for 6 commonly studied SNPs of XPA G23A, XPC C499T, C499T, XPD A751C, G312A and C156A. The results in this study showed as follows:1. The frequency of XRCC1 rs25487 genotype GG, AG, AA in lung cancer group and control group were 56.6%,37.8%,5.6%and 48.2%,41.9%,10.0%, respectivvely. No significant differences in rs25487 genotype distributions were found between the two groups((P=0.057).2. Compared with individuals with XRCC1 rs25487 GG genotype, individuals with AG genotype and A allele showed a significant decrease of risk in individuals who older than 60 years old (adOR=0.515,95%CI:0.288-0.922, P=0.026; adOR=0.531,95%CI:0.308-0.917, P=0.023.respectively).3. The frequency of XRCC1 rs 1799787 genotype CC, CT, TT in lung cancer group and control group were 55.0%,35.9%,9.2%and 51.5%,39.5%,9.0%, respectively. No significant differences in rs25487 genotype distributions were found between the two groups((P=0.668).4. The frequency of XRCC1 rs3213334 genotype CC, CT, TT in lung cancer group and control group were 82.1%,17.5%,0.4% and 80.7%,18.3%,1.0%, respectively. No significant differences in rs25487 genotype distributions were found between the two groups((P=0.687).5. The most common haplotypes of XRCC1(rs25487-rs1799782-rs3213334) were ACC, GCC and GTC。6. The frequency of XRCCl(rs25487-rsl799782-rs3213334) haplotype ACC, GCC, GTC and the others in lung cancer group and control group were 24.3%,39.4 %,26.9%,9.4% and 30.1%,30.6%,,26.9%,10.3%,respectively. A highly significant differences in XRCC1(rs25487-rsl799782-rs3213334) haplotype distributions were found between the two groups((P=0.013).7. Use the most common haplotype XRCC1ACC as reference, haplotype GCC was associated with a increased risk of lung cancer(adjusted OR,1.63; 95%CI: 1.17-2.28; P=0.004).8. The frequency of XPA rs2808668 genotype CC, CT, TT in lung cancer group and control group were19.5%,56.6%,23.9% and 30.9%,46.2%,22.9%, respectively. A highly significant differences in rs2808668 genotype distributions were found between the two groups(P=0.007).9. Compared with individuals with CC genotype, individuals with rs2808668 CT genotype and T allele had a significant increase of lung cancer risk(adjusted OR=1.77; 95%CI:1.12-2.80. P=0.014; adjusted OR-1.66; 95%CI:1.08-2.55. P=0.022 respectively).10. Compared with individuals with CC genotype, individuals with rs2808668 CT genotype and T allele had a significant increase in risk of squamous cancer (ad OR= 2.110,95%CI:1.065-4.179; P=0.032; ad OR= 2.086,95%CI:1.085-4.013, P=0.028.respectively)11. Compared with individuals with rs2808668 CC genotype, individuals with CT, TT genotype and T allele showed a significant increase of lung cancer risk in individuals who younger than 60 years old (adOR=2.255;95%CI:1.184-4.298; P= 0.013. adOR=2.181;9,95%CI:1.010-4.709;P=0.047. adOR=2.233,95% CI:1.210-4.119;P=0.01 respectively)12. Compared with individuals with rs2808668 CC genotype, individuals with CT genotype showed a significant increase of lung cancer risk in male (adOR=l.763, 95%CI:1.014-3.063, P=0.044).13. Compared with individuals with rs2808668 CC genotype, individuals with CT, TT genotype and T allele showed a significant increase of lung cancer risk in non-smokers (ad OR= 2.232,95%CI:1.153-4.320; P=0.017;ad OR= 2.032,95%CI: 0.942-4.384; P=0.071;ad OR= 2.166,95%CI:1.156-4.058, P=0.016. respectively)14. The frequency of XPA rs3176720 genotype AA, AC, CC in lung cancer group and control group were 80.5%,9.1%,0.4% and 83.1%,15.9%,1.0%, respectively. No significant differences in rs3176720 genotype distributions were found between the two groups(P=0.613).15. The most common haplotypes of XPA (rs3176720-rs2808668) were AC, AT and CT。16. The frequency of XPA(rs3176720-rs2808668)haplotype AC, AT, CT in lung cancer group and control group were 47.8%,42.2%,10.0% and 54.0% 37.0%,9.0%,respectively. No significant differences in XPA (rs3176720-rs2808668) haplotype distributions were found between the two groups((P=0.123).17. The frequency of XPC rs2733533 genotype CC, AC, AA in lung cancer group and control group were 85.7%,14.3%,0.0%,和94.0%,6.0%,0.0%, respectively. A highly significant differences in rs2733533 genotype distributions were found between the two groups(P=0.001). 18. Compared with individuals with rs2733533 CC genotype, individuals with rs2733533 A allele showed a significant increase of lung cancer risk(adjusted OR=2.48; 95%CI:1.29-4.76; P=0.006).19. Compared with individuals with rs2733533 CC genotype, individuals with A allele showed a significant increase of squamous cancer risk(ad OR= 2.612,95%CI: 1.144-5.965, P=0.023).20. Compared with individuals with rs2733533 CC genotype, individuals with A allele showed a significant increase of lung cancer risk in younger than 60 years old ad OR=6.444,95% CI:2.127-19.518; P=0.001)21. Compared with individuals with rs2733533 CC genotype, individuals with A allele showed a significant increase of lung cancer risk in male (ad OR=2.724, 95%CI:1.244-5.967, P=0.012).22. Compared with individuals with rs2733533 CC genotype, individuals with A allele showed a significant increase of lung cancer risk in non-smokers (ad OR= 5.800,95%CI:1.721-19.546; P=0.005).23. The frequency of XPC rs2228001 genotype AA, AC, CC in lung cancer group and control group were 38.2%,46.2%,15.5% and 37.5%,45.5%,16.9%, respectively. No significant differences in rs2228001 genotype distributions were found between the two groups(P=0.906).24. The frequency of XPC rs2229090 genotype CC, CG, GG in lung cancer group and control group were 46.2%,43.4%,10.4% and 50.5%,37.9%,11.9%,respetively. No significant differences in rs2228001 genotype distributions were found between the two groups(P=0.415).25. Compared with individuals with rs2229090 CC genotype, individuals with CG genotype showed a significant increase of lung cancer risk in the female (adOR=2.718,95%CI:1.334-5.536, P=0.006).26. The frequency of XPC rs3729584 genotype GG, GA, AA in lung cancer group and control group were 53.8%,38.2%,8.0%and 48.8%,41.9%,9.3%,respectively. No significant differences in rs3729584 genotype distributions were found between the two groups(P=0.501).27. Compared with individuals with rs3729584 GG genotype, individuals with AG genotype and A allele showed a significant decrease of lung cancer risk in the female(adOR=0.370,95%CI:0.178-0.773,P=0.008; adOR=0.351,95%CI:0.175-0.707, P=0.003, respectively)28. The most common haplotypes of XPC (rs2229090-rs2228001-rs2733533-rs3729584) were CCCG, CACA and GACG.29. The frequency of XPC (rs2229090-rs2228001-rs2733533-rs3729584) haplotype CCCG, CACA, GACG and the others in lung cancer group and control group were 34.1%,26.9%,26.7%,12.4% and 35.0%,30.1%,,25.9%,9.0%,respectively. No significant differences in XPC (rs2229090-rs2228001-rs2733533-rs3729584) haplotype distributions were found between the two groups(P=0.253).30. The frequency of XPD rs238415 genotype CC, CG, GG in lung cancer group and control group were30.3%.50.6%.19.1% and 29.9%.45.8%.24.3%,respetively. No significant differences in rs238415 genotype distributions were found between the two groups(P=0.318).31. Compared with individuals with rs238415 CC genotype, individuals with GG genotype showed a significant decrease of squamous cancer risk (ad OR= 0.461,95%CI:0.221-0.964, P=0.04).32. The frequency of XPD rs 1799787 genotype CC, CT, TT in lung cancer group and control group were80.9%,18.7%,0.4% and 86.4%,12.3%,1.3%, respectively. No significant differences in rs238415 genotype distributions were found between the two groups(P=0.08).33. Compared with individuals with rs1799787 CC genotype, individuals with CT genotype showed a significant increase of lung cancer risk (adjusted OR=1.89; 95%CI:1.13-3.15.P=0.015).34. Compared with individuals with rs 1799787 CC genotype, individuals with CT genotype showed a significant increase of lung cancer risk in the male (adOR=1.892,95%CI:1.008-3.551, P=0.047).35. Compared with individuals with rs 1799787 CC genotype, individuals with CT genotype showed a significant increase of lung cancer risk in light smokers(<30PY) (ad OR= 2.873,95%CI:1.036-7.970, P=0.043). 36. The most common haplotypes of XPD(rs1799787-rs238415) were CG, CC and TC.37. The frequency of XPD(rs1799787-rs238415) haplotype CG, CC, TC in lung cancer group and control group were 44.4%,45.8%,9.8%and 47.2%,45.3%,,7.5%,respectively. No significant differences in XPD(rsl799787-rs238415) haplotype distributions were found between the two groups(P=0.342).38. Compared with individuals with XPArs2808668 CC, XPCrs2733533 CC and XPDrs1 799787 CC genotypes, individuals with XPArs2808668 A allele, XPCrs2733533 A allele and XPDrs1799787 T allele showed significant increase of lung cancer risk. But after Bonferroni adjustment, the increase was not significant(adjusted OR,10.80; 95%CI:1.83-63.70.P=0.009).39. The best two-factor model consisted of XPCrs2733533 and smoking was thoughted to be the fitted model40. Compared with non-smokers with XPC rs2733533 CC genotype, the heavy smokers (≥30PY) with rs2733533 CC genotype showed a significant increase of lung cancer risk (adjusted OR=7.63; 95%CI:4.50-12.95.P<0.001). The non-smokers with A allele showed a significant increase of lung cancer risk(adjusted OR=5.80; 95%CI:1.72-19.55.P=0.005). The heavy smokers (≥30PY) with rs2733533 A allele showed a significant increase of lung cancer risk(adjusted OR=14.32; 95%CI:4.46-45.93; P<0.001).41. Interaction dendrograms showed a visualize interaction of smoking status, XRCC1rs 1799782, XPArs3176720, XPCrs2733533, rs2228001 and XPDrs238415。XRCC1rs 1799782, XPCrs2228001, XPDrs238415 and smoking have a synergistic effects on modifying risk of lung cancer. No synergistic effect was observed between XPArs3176720 and XPCrs2733533. XPArs3176720 and XPCrs2733533 respectively have interaction with smoking status, XRCClrs1799782,, rs2228001 and XPDrs238415。SNPs of XRCC1, XPA, XPC, XPD and smoking commonly contribute to lung cancer risk.42. Meta analysis showed XPC A939C CC genotype elevated lung cancer risk was verified in total population (recessive genetic model:OR=1.23,95% CI:1.05-1.44;homozygote comparison:OR=1.21,95%CI:1.02-1.43and CC vs. CA contrast:OR=1.25,95%CI:1.06-1.48)but not in Asians.43. Meta analysis showed that both the b751C allele and CC genotype increase lung cancer risk in total population and in Caucasians. (recessive genetic model:Total population:OR=1.20,95%CI:1.07-1.35;Caucasian:OR=1.19,95%CI:1.05-1.35. dominate genetic model:Total population:OR=1.10,95%CI:1.02-1.18; Caucasian: OR=1.12,95%CI:1.02-1.23.homozygote comparison:Total population:OR=1.25,95% CI:1.11-1.42; Caucasian:OR=1.24,95%CI:1.08-1.43. CC vs. CA contrast:Total population:OR=1.17,95%CI:1.03-1.32;Caucasian:OR=1.15,95%CI:1.00-1.31 and C vs. A:Total population:OR=1.10,95%CI:1.04-1.16; Caucasian:OR=1.11,95% CI:1.04-1.18). No association was found between XPD A751C and lung cancer risk in Asians and African Americans.44.Meta analysis showed that XPD G312A AA genotype increase lung cancer risk in total population, in Asians and Caucasians(recessive genetic model:Total population:OR=1.20,95%CI:1.06-1.36; Asians:OR=7.66,95%CI:1.75-33.54; Caucasians:OR=1.15,,95%CI:1.01-1.31. homozygote comparison:Total population: OR=1.19,95%CI:1.04-1.36; Asians:OR=7.68,95%CI:1.75-33.62. AA vs. AG contrast: Total population:OR=1.22,95% CI:1.07-1.40; Asians:OR=7.51,95%CI:1.71-33.04; Caucasians:OR=1.17,95%CI:1.02-1.35).45. No significant association was found between XPA G23A, XPC C499T, XPD C156A and lung cancer risk.Conclusion:(1) Different genetic polymorphisms have different effects on lung cancer susceptibility. XRCC1 (rs25487-rs1799782-rs3213334) haplotype GCC, XPA rs2808668 CT genotype and T allele, XPC rs2733533 A allele, XPD rs1799787 CT genotype increase lung cancer susceptibility. (2) SNPs of XRCC1, XPA, XPC, XPD and smoking have interaction to increase lung cancer risk. (3)Meta analysis showed that XPC A939C CC genotype remarkably increase lung cancer risk in total population but not in Asians, that both 751C allele and CC genotype significantly increase lung cancer risk in total population and in Caucasians but not in Asians and African Americans, XPD G312A AA genotype also remarkably increase lung cancer risk in total population, Asians and Caucasians.