| Glioma is an aggressive malignant primary tumor of the central nervous system.Although the only established environmental risk factor is ionizing radiation,the mechanism of glioma oncogenesis remains unclear.Given the close correlation between DNA repair and the development of glioma,and the importance of base excision repair(BER)pathway in the process of DNA repair,genetic variation of BER becomes the key factor to explore the risk of glioma.Currently,there is a lack of research on the genetic susceptibility mechanism of pediatric glioma targeting the BER pathway.Therefore,we employed molecular epidemiology methods to evaluate the impact of genetic variations on the occurrence,development,and prognosis of pediatric glioma.METHODSWe conducted a three-center case and control study based on hospital.According to the inclusion criteria,171 cases and 228 controls were collected from Guangzhou Women and Children’s Medical Center,123 cases and 132 controls were collected from Xiangya Hospital,and 20 cases and 20 controls were collected from the Second Affiliated Hospital of Wenzhou Medical University.A total of 314 children with glioma and 380 healthy controls were collected during the year from 2020 to 2021.Based on candidate gene approach,twenty single nucleotide polymorphisms(SNPs)of six core genes in the BER pathway were selected for association investigation.Taq Man genotyping was performed.Statistical analysis of experimental data was performed using SAS 9.4 software.The main statistical analysis methods include two-sided chisquare test,goodness-of-fit test,logistic regression analysis,stratified analysis,haplotype analysis,and false positive report probability.The potential effect of candidate SNPs and genes on the carcinogenesis,development and prognosis of glioma were evaluated by GTEx Portal database and the Chinese Glioma Genome Atlas Project(CGGA).RESULT1.PARP1In the single-locus association analysis,only rs2666428 of the three candidate SNPs for PARP1 was associated with pediatric glioma susceptibility(P < 0.05).In the stratified analysis,children with rs2666428 CC genotypes were associated with an increased risk of pediatric glioma when they were in the subgroups of <60 months,female,astrocytoma,embryonic tumors,and clinical stages I and I+II,compared to children with rs2666428 TT/TC genotypes(P = 0.025,adjusted OR = 10.92,95%CI =1.35-88.40;P = 0.043,adjusted OR = 8.81,95%CI = 1.07-72.72;P = 0.038,adjusted OR = 2.70,95%CI = 1.06-6.88;P = 0.004,adjusted OR = 14.08,95%CI = 2.34-84.87;P = 0.017,adjusted OR = 3.32,95%CI = 1.24-8.89;P = 0.031,adjusted OR = 2.75,95%CI = 1.10-6.86).The combined-effect analysis of PARP1 risk genotypes showed that patients with 2-3 risk genotypes had a significant increase of pediatric glioma susceptibility compared to those with 0-1 risk genotypes(P < 0.05).GTEx Portal showed that PARP1 rs2666428 T>C promoted the expression level of PARP1 in brain tissues and fibroblasts.Combined with CGGA,it was found that the increased expression level of PARP1 was significantly associated with the low survival rate of patients with primary glioma.2.h OGG1In the single-locus analysis,no statistical significance between h OGG1 candidate SNPs and pediatric glioma susceptibility was observed.However,in our stratification analysis of children under 60 months,we found that children carrying the rs159153TC/CC genotypes may reduce the risk of pediatric glioma compared to those carrying the TT genotype(P = 0.010,adjusted OR = 0.45,95%CI = 0.25-0.83).Additionally,the combined effect analysis of h OGG1 indicated that children with 2-3 protective genotypes in this age subgroup had a significantly protective effect on pediatric glioma compared to those with 0-1 genotype(P = 0.009,adjusted OR = 0.47,95%CI = 0.27-0.83).3.FEN1In the single-locus association analysis,two candidate SNPs of FEN1 were statistically associated with pediatric glioma risk(P < 0.05).In the stratified analysis of rs174538,children with rs174538 AG/GG genotypes were associated with reduced pediatric glioma risk when they were in the subgroups of <60 months,male,astrocytoma,and clinical stages I and I+II,compared with children with rs174538 AA genotypes(P = 0.044,adjusted OR = 0.62,95%CI = 0.39-0.99;P = 0.007,adjusted OR= 0.56,95%CI = 0.36-0.85;P = 0.003,adjusted OR = 0.58,95%CI = 0.40-0.82;P =0.0002,adjusted OR = 0.48,95%CI = 0.32-0.71;P = 0.002,adjusted OR = 0.58,95%CI= 0.41-0.82).In the stratified analysis of rs4246215,children with rs4246215 TG/GG genotypes were associated with increased pediatric glioma risk at all ages,both of male and female,with astrocytoma,ependymoma,and clinical stages II,III,IV,I+II and III+IV,compared with children with rs4246215 TT genotypes(P = 0.004,adjusted OR= 2.20,95%CI = 1.28-3.76;P = 0.036,adjusted OR = 1.68,95%CI = 1.04-2.71;P =0.004,adjusted OR = 2.22,95%CI = 1.29-3.82;P = 0.041,adjusted OR = 1.65,95%CI= 1.02-2.65;P = 0.013,adjusted OR = 1.66,95%CI = 1.11-2.48;P = 0.006,adjusted OR = 2.99,95%CI = 1.37-6.54;P = 0.030,adjusted OR = 2.03,95%CI = 1.07-3.86;P= 0.020,adjusted OR = 3.56,95%CI = 1.23-10.36;P = 0.030,adjusted OR = 2.41,95%CI = 1.09-5.33;P = 0.015,adjusted OR = 1.62,95%CI = 1.10-2.40;P = 0.002,adjusted OR = 2.83,95%CI = 1.48-5.40).GTEx Portal showed that FEN1 rs174538A>G promoted the expression level of FEN1 in cerebral cortex.In addition,rs174538A>G also affected the expression of other genes such as FADS1,FADS2,FADS3,MYRF and TMEM258 in various brain tissues.Meanwhile,FEN1 rs4246215 T>G also increased the expression of FEN1 in the cerebral cortex.Furthermore,rs4246215 T>G also affected the expression of FADS1,FADS2,FADS3,TMEM258 and MYRF.Combined with CGGA,it was found that the expression level of FEN1 had a significant effect on WHO grade II-IV of glioma.In addition,highly expressed FEN1 was significantly associated with lower survival in patients with primary glioma.4.APEX1In single-locus association analysis,only APEX1 rs1130409 and APEX1 rs1760944 among the three candidate SNPs of APEX1 were significantly correlated with pediatric glioma susceptibility(P < 0.05).In the stratified analysis of rs1130409,children with rs1130409 TG/GG genotypes were associated with enhanced pediatric glioma risk at ≥60 months,male,astrocytoma,clinical stage I,and I+II,compared with children with rs1130409 TT genotypes(P = 0.0005,adjusted OR = 2.15,95%CI = 1.40-3.29;P =0.012,adjusted OR = 1.75,95%CI = 1.13-2.71;P = 0.0001,adjusted OR = 2.07,95%CI= 1.43-3.01;P = 0.0007,adjusted OR = 2.07,95%CI = 1.36-3.16;P = 0.001,adjusted OR = 1.80,95%CI = 1.26-2.57).In the stratified analysis of rs1760944,children with rs1760944 TG/GG genotypes improved the risk of pediatric glioma at ≥ 60 months,male,astrocytoma,neuronal and mixed neuronal-glial tumors,clinical stage I,and I+II,compared with children with rs1760944 TT genotypes(P = 0.016,adjusted OR = 1.69,95%CI = 1.11-2.59;P = 0.028,adjusted OR = 1.63,95%CI = 1.05-2.52;P = 0.005,adjusted OR = 1.70,95%CI = 1.18-2.46;P = 0.012,adjusted OR = 4.84,95%CI = 1.42-16.53;P = 0.005,adjusted OR = 1.81,95%CI = 1.19-2.75;P = 0.003,adjusted OR =1.73,95%CI = 1.21-2.48).Combined-effect analysis of APEX1 risk genotypes showed that patients with 2-3 risk genotypes had a significant increase in pediatric glioma susceptibility compared to patients with 0-1 risk genotypes(P < 0.05).GTEx Portal showed that APEX1 rs1130409 T>G had not been found to directly affect the expression level of APEX1,but was significantly correlated with the expression level of OSGEP in various tissues.GTEx Portal also indicated that APEX1 rs1760944 T>G may reduce the expression of APEX1 in various brain tissues.However,rs1760944 T>G could promote OSGEP expression in these tissues.Combined with CGGA,it was found that the expression level of APEX1 had a significant effect on WHO grade II-IV of glioma.5.LIG3In the single-locus association analysis,we did not find any significant correlation between the three LIG3 candidate SNPs and pediatric glioma susceptibility.However,after a stratification analysis,we found that rs1052536 TT carriers conferred a significantly increased susceptibility to pediatric glioma in ependymoma,clinical grade III,compared to CC/CT genotypes carriers(P = 0.017,adjusted OR = 2.57,95%CI =1.18-5.59;P = 0.038,adjusted OR = 2.68,95%CI = 1.06-6.77).In a stratified analysis of rs4796030,we found that the CC genotype of this SNP may contribute to the risk of pediatric glioma compared to the AA/AC genotypes in the subgroup of neuronal and mixed neuronal-glial tumors(P = 0.036,adjusted OR = 2.52,95%CI = 1.06-5.95).6.XRCC1In the single-locus association analysis,only XRCC1 rs25487 and XRCC1rs3810378 of the six XRCC1 candidate SNPs were significantly correlated with pediatric glioma susceptibility(P < 0.05).In the stratified analysis of rs25487,children with CT/TT genotypes were associated with an increased risk of pediatric glioma at clinical stages III,IV,and III+IV compared to children with rs25487 CC genotypes(P= 0.017,adjusted OR = 2.43,95%CI = 1.17-5.03;P = 0.003,adjusted OR = 2.59,95%CI = 1.39-4.83;P = 0.0001,adjusted OR = 2.61,95%CI = 1.60-4.26).In the stratified analysis of rs3810378,children with rs3810378 GC/CC genotypes had a same impact on pediatric glioma susceptibility at ≥ 60 months and at clinical stages III,IV,and III+IV compared with children with rs3810378 GG genotypes(P =0.044,adjusted OR = 1.51,95%CI = 1.01-2.27;P = 0.018,adjusted OR = 2.40,95%CI = 1.16-4.98;P= 0.004,adjusted OR = 2.46,95%CI = 1.33-4.55;P = 0.0003,adjusted OR = 2.46,95%CI = 1.52-4.00).Combination analysis of risk genotypes for XRCC1 showed that patients with 5-6 risk genotypes had a significant increase in pediatric glioma susceptibility compared to patients with 0-4 risk genotypes(P < 0.05).GTEx Portal showed that XRCC1 rs25487 C>T inhibited the expression level of XRCC1 in various brain tissues.rs25487 C>T also significantly affected the expression of other genes LYPD3,PHLDB3,ZNF575,PINLYP and ZNF155 in brain tissue.Meanwhile,the GTEx Portal showed that XRCC1 rs3810378 G>C also inhibited the expression level of XRCC1 in various brain tissues.Additionally,rs3810378 G>C affected the expression of PINLYP,LYPD3,PHLDB3 and ZNF575 in these tissues.Combined with CGGA,it was found that the expression level of XRCC1 had a significant effect on WHO grade II-IV of glioma.Additionally,elevated XRCC1 expression was significantly associated with reduced survival in patients with primary glioma.CONCLUSIONCertain single nucleotide polymorphisms of the core genes in the base excision repair pathway(PARP1,FEN1,APEX1,and XRCC1)are associated with glioma susceptibility in Chinese children.The FEN1 rs174538 G allele may be a crucial target to reduce the risk of pediatric glioma. |
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