The determination of relationship between “excision repair cross-complementing group 1” (ERCC1) gene T19007C and C8092A single nucleotide polymorphisms and clinicopathological parameters in non-small cell lung cancer

DNA repair plays a key role in prevention of carcinogenesis and one of the most important DNA repair mechanisms is nucleotide excision repair (NER) pathway. This pathway includes a number of genes such as excision repair cross-complementing group 1 (ERCC1) gene which are responsible for the 5′ incision of damaged DNA. A reduced DNA repair capacity associated with ERCC1 mRNA level has been observed in lung carcinogenesis. Two single nucleotide polymorphisms (SNPs) in ERCC1 gene, T19007C (rs11615) and C8092A (rs3212986), reportedly predict to affect the mRNA of ERCC1 in non-small cell lung cancer (NSCLC). To examine the role of two common SNPs in ERCC1 gene further, we conducted this study where 80 cases histopatologically diagnosed as NSCLC were genotyped. Genomic DNA was extracted from formalin-fixed, paraffin embedded tissues and two SNPs were analyzed using real-time PCR. The distributions of TT, TC, and CC genotypes of the T19007C SNP were 40, 44 and 16%, respectively. Significantly increased frequency of the patients carrying at least one 19007C allele was observed in early stage compared to advanced stage (P = 0.002). And also, the frequency of TC and CC genotypes significantly increased in younger patients compared to older patients (P = 0.035). Regarding C8092A SNP, the distribution of CC, CA, and AA genotypes was 38, 51 and 11%, respectively. There was no significant difference in the genotype distribution between C8092A SNP and clinicopathological parameters. This study indicated that harboring at least one 19007C allele may have protective effect in NSCLC.     

Polymorphism of repair genes and cytogenetic radiation effects

For 99 healthy volunteers, the frequencies of spontaneous and y-induced (1 Gy in vitro) chromosome aberrations in blood lymphocytes were compared with the results of PCR-genotyping by 8 repair genes: XRCC1, XPD, ERCC1, APEXI, RAD23B, OGG1, ATM, Tp53 (in all, 10 polymorphic sites). The frequency of spontaneous aberrations of chromosome type increased additively with the number of copies of minor allele of excision repair gene XPD variant *2251G and *862A D (p = 0.025). The frequency of gamma-induced chromosome aberrations proved to be elevated for the carriers of a minor allele OGG1*977G (p = 0.011). The significantly elevated number of gamma-induced chromosome aberrations was also observed for the carriers of major alleles XRCC1*G1996 and XRCC1*C589 (p = 0.002).     

Association between nucleotide excision repair gene polymorphisms and chromosomal damage in coke-oven workers

The associations between several genetic polymorphisms of nucleotide excision repair genes (NER) and chromosome damage level were studied among 140 coke-oven workers exposed to a high level of polyaromatic hydrocarbons (PAHs) and 66 non-exposed workers. Seven polymorphisms with functional potential in five NER genes (ERCC1, ERCC2, ERCC4, ERCC5 and ERCC6) were genotyped in the 206 study subjects. Multivariate analysis of covariance revealed that coke-oven workers with the ERCC1 19007 CC genotype had significantly higher cytokinesis-block micronucleus frequency (CBMN) (10.5±6.8‰) than those with CT (8.1±6.6‰, p=0.01) or TT (6.6±3.7‰, p=0.05) or CT+TT genotypes (7.5±6.3‰, p=0.004). The ERCC6 A3368G polymorphism was also associated with CBMN frequency among coke-oven workers. Subjects with the AA genotype have a significantly higher CBMN frequency (10.0±6.9‰) than those with AG (6.7±4.2‰, p=0.05) or AG+GG genotypes (6.6±4.1‰, p=0.02). Stratification analysis revealed the significant associations between ERCC1 C19007T and ERCC6 A3368G, and the CBMN frequencies were only found among older workers. In addition, a significant association between ERCC2 G23591A polymorphism and CBMN frequencies was also found among older coke-oven workers. The results suggest that polymorphisms of ERCC1 C19007T, ERCC6 A3368G and ERCC2 G23591A are associated with the CBMN frequencies among coke-oven workers     

Laryngeal cancer risk and common single nucleotide polymorphisms in nucleotide excision repair pathway genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5 and XPA

Because the molecular mechanisms underlying the development of laryngeal cancer are not well understood, we conducted a case–control study to determine the association between eight common SNPs in NER pathway genes and risk of laryngeal cancer, and the association between genetic polymorphisms and environmental factors. A 1:1 matched case–control study of 176 cases and 176 controls was conducted. Laryngeal cancer cases were more likely to smoke and drink (all P values < 0.05). Subjects with the ERCC1 rs11615 CC genotype and C allele had an increased risk of laryngeal cancer. Similarly, individuals with the ERCC5 rs17655 GG genotype and G allele had an increased risk of laryngeal cancer. Gene–gene interaction analysis showed that subjects carrying ERCC1 rs11615 C allele and XPG/ERCC5 rs17655 G allele had a greatly increased risk of breast cancer. Stratified analysis revealed that the interaction between polymorphisms of ERCC1 rs11615 and ERCC5 rs17655 and smoking on cancer risk was statistically significant, and ERCC1 rs11615 polymorphisms also had a significant interaction with drinking habit. In conclusion, our study suggests that ERCC1 rs11615 and ERCC5 rs17655 polymorphisms are associated with increased risk of laryngeal cancer, and that they confer more risk among smokers and drinkers.     

ERCC1, XPD and RAI mRNA levels in lymphocytes are not associated with lung cancer risk in a prospective study of Danes

Low DNA-repair capacity has been associated with increased risk of several types of cancer. mRNA levels of the nucleotide excision repair genes ERCC1 and XPD have been shown to correlate with the DNA-repair capacity. Likewise, mRNA levels of several DNA-repair genes including ERCC1 have been shown to be lower in lymphocytes from patients with lung cancer and head and neck cancer compared with healthy persons. In these studies, the low DNA-repair gene expression levels could be either a risk factor for disease or a consequence of the same. In this nested case-cohort study, which to our knowledge, is the first prospective study of DNA-repair gene mRNA levels as predictors of lung cancer, we have investigated the occurrence of lung cancer in relation to the mRNA level of the two DNA-repair genes ERCC1 and XPD and the NF kappaB inhibitor RAI in blood samples prior to disease. Among 54,220 members of a Danish prospective cohort study, 265 lung cancer cases were identified and a sub-cohort comprising 272 individuals was used for comparison. The expression levels of the three adjacent genes were found to be highly inter-correlated, to be higher in women compared to men and to be lower in older individuals. The incidence rate ratios for lung cancer in association with one log-unit increase (natural logarithm) in mRNA levels were 1.12 (CI=0.89-1.41) for ERCC1, 1.00 (CI=0.83-1.21) for XPD and 1.25 (0.89-1.74) for RAI. In conclusion, this study indicated no association between mRNA expression of the DNA-repair genes ERCC1 and XPD and risk of subsequent development of lung cancer.     

Relationship between polymorphisms of nucleotide excision repair genes and oral cancer risk in Taiwan: evidence for modification of smoking habit

Inherited polymorphisms in DNA repair genes may be associated with differences in the repair capacity and contribute to individual's susceptibility to smoking-related cancers. Both XPA and XPD encode proteins that are part of the nucleotide excision repair (NER) pathway. In a hospital-based case-control study, we have investigated the influence of XPA A-23G and XPD Lys751Gln polymorphisms on oral cancer risk in a Taiwanese population. In total, 154 patients with oral cancer, and 105 age-matched controls recruited from the Chinese Medical Hospital in Central Taiwan were genotyped. No significant association was found between the heterozygous variant allele (AG), the homozygous variant allele (AA) at XPA A-23G, the heterozygous variant allele (AC), the homozygous variant allele (CC) at XPD Lys751Gln, and oral cancer risk. There was no significant joint effect of XPA A-23G and XPD Lys751Gln on oral cancer risk either. Since XPA and XPD are both NER genes, which are very important in removing tobacco-induced DNA adducts, further stratified analyses of both genotype and smoking habit were performed. We found a synergistic effect of variant genotypes of both XPA and XPD, and smoking status on oral cancer risk. Our results suggest that the genetic polymorphisms are modified by environmental carcinogen exposure status, and combined analyses of both genotype and personal habit record are a better access to know the development of oral cancer and useful for primary prevention and early intervention.     

Association of single nucleotide polymorphisms of ERCC1 and XPF with colorectal cancer risk and interaction with tobacco use

We investigated the association between polymorphisms in excision repair cross-complementation group 1 (ERCC1) (rs3212986, rs2298881 and rs11615) and xeroderma pigmentosum-complementation group F (XPF) (rs2276466 and rs6498486) and risk of colorectal cancer. A 1:1 matched case–control study was conducted. Conditional regression analysis indicated that individuals carrying the ERCC1 rs3212986 TT genotype and T allele had a marginally increased risk of colorectal cancer when compared with subjects with the GG genotype. Similarly, subjects carrying the rs11615 TT genotype and T allele had a marginally increased risk of colorectal cancer when compared with those with the CC genotype. Stratified analysis revealed that individuals with rs3212986 TT who were current or former smokers had a significantly increased risk of colorectal cancer, and a significant interaction was found between this SNP and cigarette smoking. In conclusion, our study suggests that rs3212986 and rs11615 polymorphisms are associated with risk of colorectal cancer in a Chinese population, particularly in smokers. This finding could be useful in revealing the genetic characteristics of colorectal cancer, and suggests more effective strategies for prevention and treatment.     

Genetic Polymorphisms of DNA Repair Gene: XRCC1 Pro206Pro and Gln632Gln in a Chinese Han Population

DNA repair genes are increasingly studied because of their critical role in maintaining genome integrity. The base excision repair (BER) pathway is a DNA repair pathway that operates on small lesions, such as oxidized or reduced bases, fragmented or nonbulky adducts, or those produced by methylating agents. The XRCC1 polymorphic system is the key gene of the BER pathway. In this study, polymorphisms of XRCC1 Pro206Pro on exon 7 and Gln632Gln on exon 17 were analyzed in a northeastern Chinese Han population. Genomic DNA extracted from 303 unrelated individuals and the PCR-RFLP technique were used to identify variants. The allele frequencies were 0.90 (A) and 0.10 (G) for XRCC1 Pro206Pro and 0.88 (G) and 0.12 (A) for XRCC1 Gln632Gln. The genotype frequencies were 0.797 (AA), 0.203 (AG), and 0 (GG) for XRCC1 Pro206Pro and 0.007 (AA), 0.222 (AG), and 0.771 (GG) for XRCC1 Gln632Gln. The expected heterozygosity and PIC were 18 and 16.38% for Pro206Pro and 21.12 and 18.89% for Gln632Gln. The two polymorphisms were in strong linkage disequilibrium (D' = 0.921, r (2) = 0.735). The results are compared with those of other reported populations. They showed marked ethnic group differences. This study provides the first analysis of the distribution of allele frequency for XRCC1 Pro206Pro and Gln632Gln in a Chinese population.     

Polymorphisms of DNA repair genes ERCC2 and XRCC1 in populations of Russia

We have conducted a comparative study of allele frequencies of single nucleotide polymorphisms (SNPs) rs1799793 and rs13181 of the ERCC2 gene as well as rs1799782 and rs25487 of the XRCC1 gene in population samples from European regions of Russia as well as in populations of Izhemsk and Priluzsk Komi and Yakuts. Significant differences in the distribution of polymorphic variants of the ERCC2 gene were demonstrated between populations of Yakuts and populations of Russians and Komi. In case of XRCC1 gene Izhemsk Komi population exhibited dissimilar allele frequencies compared to other populations.     

Association of polymorphisms in glutathione-S-Transferase and DNA repair genes with ovarian cancer risk in the Russian population

Polymorphism of glutathione-S-transferase (GSTA1, GSTM1, GSTM3, GSTP1, and GSTT1) and DNA repair (ERCC1, ERCC2, and XRCC1) genes in samples of ovarian cancer patients and healthy women of the Russian ethnic group was studied. A trend in the allele frequency variation of ERCC2 gene single nucleotide polymorphism (rs13181, A > C) was revealed. The A allele frequency was higher in the sample of patients (60,6% versus 52,9%, P = 0.058).     

Predictive value of ERCC1 single-nucleotide polymorphism in patients receiving platinum-based chemotherapy for locally-advanced and advanced non-small cell lung cancer--a pilot study

Platinum-based chemotherapy is the main type of I-line treatment of advanced and non-operative NSCLC patients without EGFR gene mutation. The excision repair cross-complementation group 1 (ERCC1) is an enzyme that executes the incision of the damaged DNA strand and removes platinum-induced DNA adducts. We investigated whether ERCC1 gene polymorphism has an effect on the response to chemotherapy and survival in 43 patients with NSCLC treated with platinum-based chemotherapy. ERCC1 19007 T>C SNPs were assessed using a PCR-RFLP methods in DNA isolated from peripheral blood lymphocytes. Disease control occurred significantly (p = 0.045) more frequently in patients with CC or CT genotype compared to patients with TT genotype. Median PFS and OS for CC homozygous were 4 and 10.5 months, 4 and 12.5 months for CT heterozygous, but only 0.3 and 1.5 months for TT homozygous patients, respectively. The probability of PFS was significantly higher (HR = 0.438, 95% CI: 0.084-0.881, p = 0.03) and probability of OS was insignificantlyhigher (HR = 0.503, 95% CI: 0.129-1.137, p = 0.084) in patients with CC or CT genotype than in patients with TT genotype. Uncommon TT genotype of ERCC1 19007 T>C polymorphism could predict poor response and shortening of progression free survival in NSCLC patients treated with platinum-based I-line chemotherapy. The analysis of this polymorphism may serve as a promising tool in the qualification of advanced NSCLC patients for appropriate chemotherapy.     

XRCC1 Arg399Gln was associated with repair capacity for DNA damage induced by occupational chromium exposure

ABSTRACT: BACKGROUND: Occupational chromium exposure may induce DNA damage and lead to lung cancer and other work-related diseases. DNA repair gene polymorphisms, which may alter the efficiency of DNA repair, thus may contribute to genetic susceptibility of DNA damage. The aim of this study was to test the hypothesis that the genetic variations of 9 major DNA repair genes could modulate the hexavalent chromium (Cr (VI))-induced DNA damage. FINDINGS: The median (P25-P75) of Olive tail moment was 0.93 (0.58-1.79) for individuals carrying GG genotype of XRCC1 Arg399Gln (G/A), 0.73 (0.46-1.35) for GA heterozygote and 0.50 (0.43-0.93) for AA genotype. Significant difference was found among the subjects with three different genotypes (P = 0.048) after adjusting the confounding factors. The median of Olive tail moment of the subjects carrying A allele (the genotypes of AA and GA) was 0.66 (0.44-1.31), which was significantly lower than that of subjects with GG genotype (P = 0.043). The A allele conferred a significantly reduced risk of DNA damage with the OR of 0.39 (95% CI: 0.15-0.99, P = 0.048). No significant association was found between the XRCC1Arg194Trp, ERCC1 C8092A, ERCC5 His1104Asp, ERCC6 Gly399Asp, GSTP1 Ile105Val, OGG1 Ser326Cys, XPC Lys939Gln, XPD Lys751Gln and DNA damage. CONCLUSION: The polymorphism of Arg399Gln in XRCC1 was associated with the Cr (VI)- induced DNA damage. XRCC1 Arg399Gln may serve as a genetic biomarker of susceptibility for Cr (VI)- induced DNA damage.     

Polymorphisms in DNA Repair Gene and Susceptibility to Glioma: A Systematic Review and Meta-Analysis Based on 33 Studies with 15 SNPs in 9 Genes

At present, many publications have evaluated the correlation between the DNA repair gene polymorphisms and glioma susceptibility. However, the results remain inconclusive. The aim of this research is to exhaustively assess the association of genetic polymorphisms in DNA repair genes with glioma risk in human. Meta-analysis method was conducted, and 33 studies with 15 SNPs in 9 genes were included (12553 glioma cases and 17178 controls). Correlation strength was evaluated by odds ratio with a 95 % confidence interval. Rs1799782 T allele and rs25487A allele might bring about higher risk of glioma in Asian population. Rs1805377 G allele was an increased risk genetic factor of glioma. Asian carried with rs3212986 A allele was more likely to have glioma. Rs1800067 G allele was a risk factor of developing glioma. Carriers with rs12917 CC genotype in MGMT gene had higher risk of glioma in Caucasian than other non-CC genotype carriers. Carriers with rs1136410 T allele in PARP1 gene could more likely to develop glioma in Caucasian. This meta-analysis suggests that glioma susceptibility is associated with rs1799782 and rs25487 of X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), rs1805377 of XRCC4, rs1800067 of excision repair cross-complementing rodent repair deficiency complementation group 4 (ERCC4) and rs3212986 of ERCC1 in Asian population, and rs12917 of O-6-methylguanine-DNA methyltransferase (MGMT) and rs1136410 of poly(ADP-ribose) polymerase 1 (PARP1) in Caucasian population.     

DNA repair capacity: inconsistency between effect of over-expression of five NER genes and the correlation to mRNA levels in primary lymphocytes

We have previously shown that high DNA repair capacity protects psoriasis patients against chemically induced basal cell carcinoma [Dybdahl et al. Mutat. Res. 433 (1999) 15-22]. We have used the same study persons to investigate the correlation between expression of eight genes involved in nucleotide excision repair and DNA repair capacity. mRNA levels of XPA, XPB, XPC, XPD, XPF, XPG, CSB and ERCC1 in primary lymphocytes from 33 individuals were quantified by dot-blots and normalized to beta-actin. ERCC1 and XPD mRNA quantities were highly correlated (r=0.89; P<10(-11)) while XPA, XPB, XPC, XPG, XPFand CSB mRNAs were moderately correlated (r=0.2-0.7). Thus, the mRNA expressions seem to fall in at least two groups. There was a three to sevenfold variation in the expression levels of the mRNAs. This is in contrast to the more than a hundredfold variation in mRNA levels reported in cancer patients.DNA repair capacity was measured in a host cell reactivation assay, where primary lymphocytes were transfected with an UV-irradiated plasmid encoding firefly-luciferase. Only ERCC1 and XPD mRNA levels correlated with the DNA repair capacity (P<0.03). In order to see if ERCC1 or XPD activity was limiting for DNA repair, we cotransfected with plasmids encoding NER genes, thus over-expressing either XPB, XPC, XPD, CSB or ERCC1 in the host cell reactivation assay. Only XPB over-expression increased DNA repair capacity. Thus, there is no indication that neither XPD nor ERCC1 limits the DNA repair capacity. However, our results indicate that ERCC1 and XPD mRNA levels may be used as a proxy for DNA repair capacity in lymphocytes.     

HapMap-based study of a region encompassing ERCC1 and ERCC2 related to lung cancer susceptibility in a Chinese population

DNA repair genes play a crucial role in carcinogenesis. The paper aims to explore if common variants in ERCC1 are involved in lung cancer susceptibility. A Chinese case-control study included 339 lung cancer cases and 358 controls using five haplotype-tagging SNPs (htSNPs) (rs3212980, rs3212964, rs3212961, rs11615 and rs2298881) from the HapMap database, capturing 95% of the common haplotypic diversity of ERCC1. A combined analysis of eleven htSNPs covering ERCC2 and ERCC1 was performed. No significant association between individual htSNPs and lung cancer susceptibility was observed. There were interactions between rs3212961 and rs2298881and smoking duration (P=0.03 and P=0.01, respectively). Thus, the variant alleles of rs3212961 [OR (95% CI)=1.81(1.03-3.17), P=0.04] and rs2298881 [OR (95% CI)=2.16(1.26-3.70), P=0.005] were associated with risk of lung cancer among long-term smokers (>20 years) but not among never smokers and short-term smokers. No significant associations with lung cancer susceptibility were observed for global or individual haplotypes defined by five htSNPs of ERCC1. A highly differential distribution of haplotypes based on eleven htSNPs covering ERCC2 and ERCC1 were found (global test P=4.3×10(-5)). After Bonferroni correction, haplotypeER2+1-1 [OR (95% CI)=3.63 (1.39-9.47), P=0.005, marginally] and haplotypeER2+1-8 [OR (95% CI)=4.46 (2.03-9.79), P=5.6×10(-5), strongly] were associated with increased risk of lung cancer. The diplotype analysis with haplotypeER2+1-8 was also statistically significant (P<0.001). Haplotype analysis of pathological subtypes revealed that htSNPs of both genes may mainly influence the risk of lung adenocarcinoma. Strong linkage disequilibrium exist in two regions encompassing ERCC2 and ERCC1. These data suggest that common genetic variations in ERCC1 may influence increased risk of smoking-related lung cancer and one of the causative effectors may locate around or within ERCC2.     

The ERCC1/XPF endonuclease is required for efficient single-strand annealing and gene conversion in mammalian cells

The mammalian ERCC1-XPF endonuclease has a suggested role in the repair of DNA double-strand breaks (DSB) by single-strand annealing (SSA). Here, we investigated the role of ERCC1 in homologous recombination in mammalian cells, and confirm a role of ERCC1 in SSA. Interestingly, we also report an unexpected role for ERCC1 in gene conversion. This provides support that gene conversion in mammalian somatic cells is carried out through synthesis-dependent strand annealing, rather than through a double Holliday Junction mechanism. Moreover, we find low frequencies of SSA and gene conversion in G1-arrested cells, suggesting that SSA is not a frequent DSB repair pathway in G1-arrested mammalian cells, even in the presence of perfect repeats. Furthermore, we find that SSA is not influenced by inhibition of CDK2 (using Roscovitine), ATM (using Caffeine and KU55933), Chk1 (using CEP-3891) or DNA-PK (using NU7026).     

The Effect of XPD/ERCC2 Polymorphisms on Gastric Cancer Risk among Different Ethnicities: A Systematic Review and Meta-Analysis

Background

Potential xeroderma pigmentosum group D (XPD), also called excision repair cross-complimentary group two (ERCC2), Lys751Gln and Asp312Asn polymorphisms have been implicated in gastric cancer risk among different ethnicities.

Methods

We aimed to explore the effect of XPD Lys751Gln and Asp312Asn polymorphisms on the susceptibility to gastric cancer among different ethnicities through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. 13 studies were ultimately eligible for the meta-analysis of Lys751Gln polymorphism and 9 studies for the meta-analysis of Asp312Asn polymorphism. We adopted the most probably appropriate genetic model (recessive model) for both Lys751Gln and Asp312Asn polymorphisms. Potential sources of heterogeneity were sought out via subgroup and sensitivity analyses, and publication biases were estimated.

Results

Statistically significant findings were apparently noted in Asians but not in Caucasians for both XPD Lys751Gln and XPD Asp312Asn polymorphisms. A statistically significant finding could be seen in noncardia-type gastric cancer for XPD Lys751Gln polymorphism. A statistically significant finding could also be seen in high quality subgroup, small-and-moderate sample size subgroup, articles published after 2007, or PCR-RFLP genotyping subgroup for XPD Asp312Asn polymorphism.

Conclusions

Our meta-analysis indicates that XPD Gln751Gln (CC) genotype and Asn312Asn (AA) genotype may seem to be more susceptible to gastric cancer in Asian populations but not in Caucasian populations, suggesting that the two genotypes may be important biomarkers of gastric cancer susceptibility for Asian populations, the assumption that needs to be further confirmed in well-designed studies among different ethnicities. Gln751Gln (CC) genotype may also be associated with noncardia-type gastric cancer risk, which should also be confirmed among different ethnicities in the future.     

ERCC1 and ERCC2 Haplotype Modulates Induced BPDE-DNA Adducts in Primary Cultured Lymphocytes

Background

Benzo[a]pyrene(B[a]P), and its ultimate metabolite Benzo[a]pyrene 7,8-diol 9,10-epoxide (BPDE), are classic DNA damaging carcinogens. DNA damage caused by BPDE is normally repaired by Nucleotide Excision Repair (NER), of which ERCC1 and ERCC2/XPD exert an indispensable role. Genetic variations in ERCC1 and ERCC2 have been related to DNA repair efficiency. In this study we used lymphocytes from healthy individuals to show that polymorphisms in ERCC1 and ERCC2 are directly associated with decreased DNA repair efficiency.

Methods

ERCC1 (rs3212986 and rs11615) and ERCC2 (rs13181, rs1799793 and rs238406) were genotyped in 818 healthy Han individuals from the northeast of China. BPDE induced DNA adducts in lymphocytes were assessed by high performance liquid chromatography (HPLC) in 282 randomly selected participants. The effect of ERCC1 rs3212986 and ERCC2 rs238406 on DNA damage caused by B[a]P was assessed with a modified comet assay.

Results

We found that the variant genotypes of ERCC1 rs3212986 and ERCC2 rs238406 were associated with the high levels of BPDE-DNA adducts. Especially ERCC1 rs3212986 A-allele variant was significantly associated with the high BPDE-DNA adducts. Haplotype analysis showed that the ERCC1 haplotype AC (OR = 2.36, 95% CI = 1.84–2.97), ERCC2 haplotype AGA (OR = 1.51, 95% CI = 1.06–2.15) and haplotype block AGAAC (OR = 5.28, 95% CI = 2.95–9.43), AGCAC (OR = 1.35 95% CI = 1.13–1.60) were linked with high BPDE-DNA adducts. In addition, we found that the combined minor alleles of ERCC1 rs3212986 and ERCC2 rs238406 were associated with a reduced DNA repair capacity.

Conclusions

Our results suggest that the variant genotypes of ERCC1 rs3212986 and ERCC2 rs238406 are associated with decreased repair efficiency of BPDE induced DNA damage, and may be predictive for an individual’s DNA repair capacity in response to environmental carcinogens.     

Association of ERCC1 C8092A and ERCC2 Lys751Gln Polymorphisms with the Risk of Glioma: A Meta-Analysis

Objectives

To comprehensively evaluate the association of ERCC1 C8092A and ERCC2 Lys751Gln polymorphisms with the risk of glioma.

Methods

Potential studies were searched and selected through the Pubmed/MEDLINE, EMBASE, the China National Knowledge Infrastructure (CNKI) platforms, WanFang and VIP database up to June 2013. Two investigators independently reviewed full text and included studies met inclusion criteria. Combined odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated in a fixed-effects model or a random-effects model according to results of heterogeneity test. All analyses were performed by Revman 5.2 and Stata 10.0 software.

Results

A total of 10 studies were included in our meta-analysis, including 3,580 glioma patients and 4,728 controls. Overall, ERCC1 C8092A polymorphism was associated with the risk of glioma (AA vs. CC: OR = 1.29, 95%CI: 1.07–1.55, P = 0.01; recessive model: OR = 1.29; 95% CI: 1.07–1.55, P = 0.01). When stratified by ethnicity, significant association was only observed in the Chinese population (AA vs. CC: OR = 1.37, 95%CI: 1.03–1.81, P = 0.03; recessive model: OR = 1.34; 95% CI: 1.02–1.75, P = 0.04). For ERCC2 Lys751Gln polymorphism, no significant association was found between ERCC2 Lys751Gln polymorphism and the risk of glioma in different genetic models. A significant association of ERCC2 Lys751Gln polymorphism with the risk of glioma was identified in the Caucasian population under recessive model (OR = 0.87; 95% CI: 0.78–0.98, P = 0.02), but not in the Chinese population.

Conclusion

This meta-analysis suggested that the AA genotype of ERCC1 C8092A polymorphism might increase the susceptibility of glioma in the Chinese population. And the TT genotype of ERCC2 Lys751Gln polymorphism may decrease the risk of glioma in the Caucasian population. But the small number of studies and moderate methodological quality require cautious interpretation of the study results.     

Associations between XRCC1 and ERCC2 polymorphisms and DNA damage in peripheral blood lymphocyte among coke oven workers.

A wide variety of base damages and single-strand breaks formed by reactive oxygen species during metabolic activation of polycyclic aromatic hydrocarbons (PAHs) have been recognized to be involved in PAH carcinogenesis. In this study, alkaline comet assay was used to detect the DNA damage in peripheral blood lymphocytes among 143 coke-oven workers and 50 non-coke-oven workers, and the effects of genetic polymorphisms of XRCC1 and ERCC2 genes on DNA damage were evaluated. The olive tail moment was significantly higher in coke-oven workers than in non-coke-oven workers (2.6, 95% CI=2.1-3.3 versus 1.0, 95% CI=0.8-1.2, p<0.01), and significant correlation between ln-transformed urinary 1-OHP and ln-transformed olive tail moment was found in total population (n=193, Pearson's r=0.393, p<0.001) and in coke-oven workers (n=143, Pearson's r=0.224, p=0.007). The olive tail moment was significantly higher in coke-oven workers with GA genotype of G27466A polymorphism of XRCC1 than those with GG genotype (4.6, 95% CI=2.5-8.7 versus 2.4, 95% CI=1.9-2.9, p<0.01 with adjustment for covariates). No significant associations between C26304T, G28152A and G36189A polymorphisms of XRCC1 and G23591A and A35931C polymorphisms of ERCC2 and olive tail moment were found in both groups. The study showed that the alkaline comet assay is a suitable biomarker in the detection of DNA damage among coke-oven workers and it suggested that the A allele of G27466A polymorphism of XRCC1 may be associated with decreased DNA repair capacity toward PAH-induced base damage and strand breaks.