Genetic Susceptibility Of Dna Double Strand Break Repair Pathway Gene Polymorphisms And Gliomas

PartⅠApproximately 9% of human cancers are brain tumors, of which 90% are gliomas.And there is a tendency toward higher incidence rates in more developed,industrialized cities or countries. Though the etiology of gliomas remains unclear,exposure to ionizing radiation has been identified as the only established risk factor.Ionizing radiation is known to cause DNA damage, including single-strand anddouble-strand DNA breaks (DSBs), and the un-repair of DNA damage, particularlyDSBs, may cause chromosome aberrations.We hypothesized that polymorphisms of the five critical candidate genes (XRCC5,XRCC6, XRCC7, LIG4 and XRCC4) involved in the NHEJ pathway may contribute tosusceptibility to glioma. We used a haplotype-based approach to investigate the role of42 tagging single nucleotide polymorphisms (tSNPs) of XRCC5, XRCC6, XRCC7,LIG4 and XRCC4 in 771 glioma patients and 752 healthy controls. The genotype andhaplotypes difference between cases and controls were calculated, andgene-environment, gene-gene interactions were also evaluated.We found that, in the single locus analysis, glioma risk was statisticallysignificantly associated with three XRCC5 tSNPs(SNP1, SNP6 and SNP7, P=0.005,0.042 and 0.003, respectively), one XRCC6 tSNP (SNP4, P=0.044), one XPCC4 tSNP(SNP7, P=0.016), one LIG4 tSNP (SNP2, P=0.009). The significance remained forXRCC5 SNP1 (P=0.040) and SNP7 (P=0.024), and LIG4 SNP2 (P=0.045) after theBonferroni correction. Further stratified analyses revealed, compared with the commonhomozygous, the protective effects of XRCC5 SNP1 and the risky effects of SNP7variant were both more evident in the adults, diffuse and anaplastic astrocytomassubgroups, whereas the risky effects of LIG4 SNP2 were more evident in adults andpatients with glioblastoma.Haplotype analysis revealed that, compared with the most common haplotype, onerisk haplotype "AAATC" (adjusted OR=1.33, 95% CI=1.06-1.70), and twoprotective haplotypes "CGGTT" (adjusted OR=0.66, 95% CI=0.52-0.81) and "CAGTT" (adjusted OR=0.60, 95% CI=0.43-0.84) were found for XRCC5; The riskhaplotype "CGAAA" in XRCC6 had a 2.36-fold increased risk of gliomas (adjusted OR=2.36, 95% CI=1.59-3.54); For LIG4, two risk haplotypes 1-B (adjusted OR=1.30,95% CI=1.04-1.61) and 1-C (adjusted OR=1.52, 95% CI=1.08-2.13) were foundfor block 1. For XRCC4, one risk haplotype 2-C (adjusted OR=1.64, 95% CI=1.23-2.17) and one protective haplotype 2-E (adjusted OR=0.21, 95% CI=0.12-0.37)were found for block 2; and in block 4, two risk haplotype 4-B (adjusted OR=1.28,95% CI=1.03-1.59), 4-C(adjusted OR=1.61, 95% CI=1.19-2.22) and a highlyprotective haplotype 4-D with an 10-fold reduction effect on glioma risk (adjusted OR=0.10, 95% CI=0.05-0.19) were identified. Furthermore, global score test alsoshowed statistically significant differences in haplotype profile between case patientsand control subjects for XRCC5 (P＜0.000), XRCC6 (P＜0.000), LIG4 block 1(P=0.011), XRCC4 block 2 and block 4 (both P＜0.0001).The MDR gene-gene interactions analysis indicated that the 3-locus (i.e., XRCC5SNP4 and SNP5, and XRCC6 SNP5) was the best interaction model for predicting riskof glioma in both KU complex and DNA-PK complex; and the 3-locus model was thebest model (i.e., LIG4 SNP4 and, XRCC4 SNP12 and SNP15)for predicting risk ofglioma in LIG4/XRCC4 complex.In conclusion, genetic variants of the genes involved in the NHEJ pathway mayplay a role in the etiology of glioma. Furthermore, the interaction analysis suggestedthat the association was even stronger when gene-gene interactions within the DNA-PKand LIG4/XRCC4 complex were considered. PartⅡBasic strategies for the repair of DSBs involve either nonhomologous end joining(NHEJ) or homologous recombination repair(HRR). In the present study, weinvestigate the role of 17 SNPs (mostly functional polymorphisms) from 13 importantcandidate genes involved in the HR pathway in 771 glioma patients and 752 healthycontrols. The genotype and haplotypes difference between cases and controls werecalculated, and gene-environment, gene-gene interactions were also evaluated.We found that, in the single locus analysis, glioma risk were statisticallysignificantly associated with XRCC3 rs861530 and RAD54L rs1048771 (P=0.006 and0.018, respectively). Further stratified analyses showed, the risk effects of XRCC3rs861530 AG/GG genotype were more evident in the adults, diffuse and anaplasticastrocytomas subgroups, whereas the risk effects of RAD54L rs1048771 TT genotypewere more evident in adults and patients with glioblastoma subgroups.Haplotype analysis revealed that, two risk haplotype "CGG" (adjusted OR=1.34,95% CI=1.11-1.63) and "TGA" (adjusted OR=1.58, 95% CI=1.02-2.60) werefound for XRCC3 block1 which consisted of rs3212092, rs861531 and rs861530.Further global score test also showed statistically significant differences in haplotypeprofile between case patients and control subjects for XRCC3 (P=0.0009).The MDR gene-gene interactions analysis indicated that the 4-locus (i.e., ATMrs227062, MRE11 rs 10831234, RAD50 rs2066960, and NBS1 rs 1805794) was the bestinteraction model for predicting risk of glioma in the ATM/MRN complex, but theinteraction graph didn't detect these interaction effects among them. In HR pathway,there are significant interaction effects for predicting risk of glioma between the followpairwise SNPs: XRCC3 rs861531 and rs861530; XRCC3 rs861531 and ATM rs227062;XRCC3 rs861530 and RAD52 rs11226; RAD52 rs11226 and XRCC1 rs1799782;XRCC2 rs3218556 and RAD50 rs2066960.The above results suggested that genetic variants of the genes involved in the HRpathway may play a role in the etiology of glioma.