| Objective: Because of the importance of maintaining genomic integrity in the general and specialized functions of cells as well as in the prevention of carcinogenesis, genes coding for DNA repair molecules have been proposed as candidate cancer-susceptibility genes. XPC and XPD gene are Nucleotide Excision Repair (NER) genes. This study was designed to investigate the correlation of single nucleotide polymorphisms (SNPs), C/T in exon 8 and A/C in exon 15 and PAT insertion/deletion in intron 9 of XPC gene, G/A in exon 10 and A/C in exon 23 of XPD gene, to susceptibilities of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) in a population of high incidence region of Hebei Province.Methods: This population-based case-control study included 580 cancer patients (327 with ESCC and 253 with GCA) and 612 healthy controls. Genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. Polymorphisms of XPC and XPD gene were analyzed by PCR-restriction fragment length polymorphism analysis (RFLP) and primer-introduced restriction analysis PCR (PIRA-PCR).Statistical analysis was performed using SPSS11.5 software package. P<0.05 was considered significant for all statistical analyses. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in the control group using Chi-square test. Comparison of the XPC and XPD genotype, allelotype and haplotype distribution in cancer patients and healthy controls was performed by means of two-sided contingency tables using Chi-square test. The XPC and XPD haplotype frequencies and linkage disequilibrium coefficient were estimated by using EH linkage software and 2LD software. The odds ratio (OR) and 95% confidence Interval (CI) were calculated using an unconditional logistic regression model and adjusted by age, gender, smoking status and family history of upper gastrointestinal cancer (UGIC) accordingly.Results1 The frequency of positive family history of upper gastrointestinal cancer (UGIC) in ESCC (48.0%) and GCA (47.8%) patients was significantly higher than that in healthy controls (34.2%) (χ2=17.22 and 14.19, P=0.00). Family history of UGIC may increase the risk of developing ESCC and GCA (age, gender and smoking status adjusted OR=1.80 and 1.75, 95%CI=1.36~2.38 and 1.29~2.36, respectively).2 The distribution of XPC SNPs genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (all P values are above 0.05). The allelotype and genotype distribution of the XPC C/T SNP in exon 8 in the overall ESCC patients was not significantly different from that in healthy controls (P>0.05). However, frequency of the XPC T allele in GCA patients was 26.5%, which was significantly lower than that in healthy controls (32.5%) (χ2=6.12, P=0.01). Compared with individuals with the C/C genotype, individuals with the C/T genotype had significantly lower risk to develop GCA (age, gender, smoking status and family history of UGIC adjusted OR=0.62, 95%CI=0.45~0.84). When stratified by smoking status, compared with individuals with the C/C genotype, individuals with the C/T genotype in smoker group had lower risk in developing GCA (age, gender, family history of UGIC adjusted OR=0.57, 95%CI =0.36~0.91). When stratified by family history of UGIC, compared with individuals with C/C genotype, individuals with the C/T genotype in the group without family history of UGIC had lower risk in developing ESCC and GCA (age, gender, smoking status adjusted OR=0.67 and 0.57, 95%CI=0.46~0.99 and 0.37~0.88, respectively).3 The allelotype and genotype distributions of the XPC A/C SNP in exon 15 in the overall ESCC and GCA patients were not significantly different from that in healthy controls (P>0.05). When stratified by smoking status, compared with individuals with the A/A genotype, individuals with the C/Cgenotype in non-smoker group had higher risk in developing ESCC (age, gender, family history of UGIC adjusted OR=2.05, 95%CI =1.15~3.66). When stratified by family history of UGIC, XPC A/C SNP in exon 15 had no significant influence on the risk of ESCC and GCA.4 The allelotype and genotype distributions of the XPC PAT -/+ SNP in intron 9 in the overall ESCC and GCA patients were not significantly different from that in healthy controls (P>0.05). When stratified by smoking status, compared with individuals with the PAT -/- genotype, individuals with the PAT +/+ genotype in non-smoker group had higher risk in developing ESCC (age, gender, family history of UGIC adjusted OR=1.79, 95%CI =1.00~3.18). When stratified by family history of UGIC, XPC PAT -/+ SNP in intron 9 had no significant influence on the risk of ESCC and GCA.5 The combind analysis of the SNPs of XPC gene showed that they were in linkage disequilibrium. Thus, the C allele in exon 8 and the A allele in exon 15 were in linkage disequilibrium, the C allele in exon 8 and the PAT- allele in intron 9 were in linkage disequilibrium, the PAT- allele in intron 9 and the A allele in exon 15 were in linkage disequilibrium. The combined analysis of the three XPC SNPs indicated that the C/A/- haplotype was the most frequent haplotype in the population, which was 28.4%. The C/A/+ and C/C/+ haplotype significantly reduced the risk of ESCC (OR=0.71 and 0.54, 95%CI=0.52~0.97 and 0.36~0.83, respectively). The haplotype distribution in GCA patients was not clearly different from that in healthy controls (P>0.05).6 The distribution of XPD SNPs genotypes among healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (all P values are above 0.05). The allelotype and genotype distributions of the XPD G/A SNP in exon 10 in the overall ESCC and GCA patients were not significantly different from that in healthy controls (P>0.05). When stratified by smoking status and family history of UGIC, XPD G/A SNP in exon 10 had no significant influence on the risk of ESCC and GCA.7 The allelotype and genotype distributions of the XPD A/C SNP in exon 23 in the overall ESCC and GCA patients were not significantly different from that in healthy controls (P>0.05). When stratified by smoking status, compared with individuals with the A/A genotype, individuals with the C allele (A/A or C/C genotype) in non-smoker group had lower risk in developing GCA (age, gender and family history of UGIC adjusted OR=0.50, 95%CI =0.26~0.97). When stratified by family history of UGIC, XPD A/C SNP in exon 23 had no significant influence on the risk of ESCC and GCA.8 The combined effect of XPD G/A and A/C SNPs on ESCC and GCA was analyzed by EH and 2LD software. It was shown that the XPD G allele in exon 10 and the A allele in exon 23 were in linkage disequilibrium. The G/A haplotype was the most frequent haplotype in the population, which was 85.9%. The haplotype distribution in ESCC and GCA patients was not clearly different from that in healthy controls (P>0.05).Conclusions1 Family history of UGIC increases the risk of developing ESCC and GCA.2 Compared with individuals with C/C genotype in XPC exon 8, individuals with C/T genotype had significantly lower risk to develop GCA, especially in individuals in smoker group and in the group without family history of UGIC. Compared with individuals with C/C genotype, Individuals with C/T genotype in the group without family history of UGIC had significantly lower risk to develop ESCC, too.3 Compared with individuals with A/A genotype in XPC exon 15, individuals with C/C genotype in non-smoker group had significantly higher risk to develop ESCC.4 Compared with individuals with PAT -/- genotype in XPC intron 9, individuals with PAT +/+ genotype in non-smoker group had significantly higher risk to develop ESCC.5 The combind analysis of the SNPs of XPC gene showed that they were in linkage disequilibrium. Thus, the C allele in exon 8 and the A allele in exon 15 were in linkage disequilibrium, the C allele in exon 8 and the PAT- allele in intron 9 were in linkage disequilibrium, the PAT- allele in intron 9 and the A allele in exon 15 were in linkage disequilibrium. The combined analysis of the three XPC SNPs indicated that the C/A/+ and C/C/+ haplotype significantly reduced the risk of ESCC and the haplotype distribution had no influence on the risk of GCA.6 The XPD G/A polymorphism alone may not be associated with ESCC and GCA development.7 Compared with individuals with A/A genotype in XPD exon 23, individuals with the C allele (A/A or C/C genotype) in non-smoker group had significantly lower risk to develop GCA.8 The G allele in exon 10 and the A allele in exon 23 in XPD gene were in linkage disequilibrium. The haplotype distribution had no influence on the risk of ESCC and GCA.
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