DNA Repair Gene XRCC1 Polymorphisms Research Articles

DNA repair gene XRCC1 polymorphisms and haplotypes in diffuse large B-cell lymphoma in a Korean population

DNA repair gene XRCC1 polymorphisms could lead to defective DNA repair and increased risk of lymphoma. This study was performed to evaluate the effect of polymorphisms and haplotypes of the XRCC1 gene on the risk of diffuse large B-cell lymphoma (DLBCL) and treatment outcomes after rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) chemotherapy in a Korean population. Carriers of XRCC1 194 variant genotypes had a significantly increased risk of DLBCL [adjusted odds ratio (OR), 1.57; 95% confidence interval (95% CI), 1.06–2.32; P = 0.028] among three polymorphisms of XRCC1 Arg194Trp, Arg280His, and Arg399Gln in 145 patients with DLBCL and in 515 healthy controls. Three polymorphisms of XRCC1 showed very strong linkage disequilibrium (LD) and consisted of one haploblock. The frequency of XRCC1 haplotype A (194Arg-280Arg-399Arg) was significantly lower in DLBCL patients compared to controls (OR, 0.60; 95% CI, 0.15–0.81; P = 0.001). The frequency of XRCC1 haplotype B (194Arg-280Arg-399Gln) was significantly higher in DLBCL patients compared to controls (OR, 1.38; 95% CI, 1.05–1.80; P = 0.019). The association between haplotype A and decreased risk of DLBCL was stable on permutation testing ( P = 0.038). However, no relation was noted between these variant genotypes and treatment outcomes in DLBCL patients treated with R-CHOP chemotherapy. These findings suggest that haplotype A of XRCC1 plays a protective role against development of this disease and the haplotype estimation is advantageous for association studies of various cancers showing strong LD.

DNA repair gene XRCC1 polymorphisms and non-Hodgkin lymphoma risk in a Chinese population

Genetic polymorphism in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with cancer risks. This hospital-based case–control study examined whether polymorphism in the DNA repair gene x-ray repair cross-complementing groups 1 ( XRCC1 Arg194Trp [C→T], Arg280His [G→A], and Arg399Gln [G→A]) played a role in susceptibility to non-Hodgkin’s lymphoma (NHL) in the Chinese population. We genotyped these polymorphisms for 221 histopathologically confirmed NHL cases and 254 age- and sex-matched healthy control cases in China. No studied polymorphism alone was shown to be related to the risk of NHL or each histologic subtype of NHL. When stratified by smoking status, however, the XRCC1Arg399Gln variant genotypes (homozygotes and heterozygotes) were associated with a 3.0-fold risk of follicular lymphoma among heavy smokers (95% confidence interval: 1.16–7.82; P = 0.02). Further large-scale studies would confirm this association and clarify marginally significant trends in XRCC1 polymorphism combinations for an increased risk for NHL.

DNA repair gene XRCC1 polymorphisms and bladder cancer risk

BackgroundCigarette smoking and chemical occupational exposure are the main known risk factors for bladder transitional cell carcinoma (TCC). Oxidative DNA damage induced by carcinogens present in these exposures requires accurate base excision repair (BER). The XRCC1 protein plays a crucial role in BER by acting as a scaffold for other BER enzymes. Variants in the XRCC1 gene might alter protein structure or function or create alternatively spliced proteins which may influence BER efficiency and hence affect individual susceptibility to bladder cancer. Recent epidemiological studies have shown inconsistent associations between these polymorphisms and bladder cancer. To clarify the situation, we conducted a comprehensive analysis of 14 XRCC1 polymorphisms in a case-control study involving more than 1100 subjects.ResultsWe found no evidence of an association between any of the 14 XRCC1 polymorphisms and bladder cancer risk. However, we found carriage of the variant Arg280His allele to be marginally associated with increased bladder cancer risk compared to the wild-type genotype (adjusted odds ratio [95% confidence interval], 1.50 [0.98–2.28], p = 0.06). The association was stronger for current smokers such that individuals carrying the variant 280His allele had a two to three-fold increased risk of bladder cancer compared to those carrying the wildtype genotype (p = 0.09). However, the evidence for gene-environment interaction was not statistically significant (p = 0.45).ConclusionWe provide no evidence of an association between polymorphisms in XRCC1 and bladder cancer risk, although our study had only limited power to detect the association for low frequency variants, such as Arg280His.

The DNA repair gene XRCC1 and genetic susceptibility of lung cancer in a northeastern Chinese population

To evaluate the effect of DNA repair gene XRCC1 polymorphisms on the risk of lung cancer in a northeastern Chinese population, we studied five cSNPs in the XRCC1 gene, three that lead to non-synonymous changes: Arg194Trp, Arg280 His and Arg399Gln and two that lead to synonymous changes: Pro206Pro and Gln632Gln. A hospital-based case-control study consisted of 247 lung cancer cases and 253 cancer-free controls matched on age, gender and ethnicity. PCR-RFLP was used for genotyping. Carriers of the minor G-allele of Pro206Pro were at significantly increased risk of lung cancer (adjusted OR=1.96, 95% CI=1.26-3.06, P=0.003). Stratified analyses revealed a significantly decreased risk of lung cancer associated with the AG/AA genotype of Arg280His (AG+AA versus GG, OR=0.38, 95% CI=0.19-0.75, P=0.005) among never smokers, although there was no interaction between Arg280His and smoking. In a haplotype analysis, a haplotype defined by Arg194Trp(C)-Pro206Pro(G)-Arg280His(G)-Arg399Gln(G)-Gln632Gln(G) was associated with increased risk of lung cancer (OR=28.60, 95% CI=2.49-331.31, P=4.45x10(-5)). No associations were observed for the other polymorphisms or haplotypes. Our results suggest that the XRCC1 Pro206Pro polymorphism or the haplotype encompassing the minor allele may contribute to genetic susceptibility for lung cancer in this northeastern Chinese population. To our knowledge, this is first report that XRCC1 Pro206Pro influences cancer risk.

Association of DNA repair gene XRCC1 polymorphisms with head and neck cancer in Korean population.

Squamous cell carcinoma of the head and neck (SCCHN), which is relatively prevalent in Korea, is believed to be induced by environmental carcinogens and host genetic factors. Accumulating evidence has shown that genetic differences in DNA repair capacity resulting from genetic polymorphism influence the risk of environmental carcinogenesis. We therefore examined the associations of genetic polymorphisms in the DNA repair genes XRCC1 with the risk of SCCHN in a Korean population (hospital-based, case-control study; 147 cases and 168 controls). Three known polymorphisms in the XRCC1 gene were genotyped: R194W(C>T) in exon 6, R280H(G>A) in exon 9 and R399G(G>A) in exon 10. Although no significant associations were apparent with R280H(G>A) and R399G(G>A), a highly significant association (p = 0.0005) of R194W(C>T) with the increased risk (OR = 2.61; 95% CI 1.53-4.46) of SCCHN was detected among patients and normal controls under dominant model. The frequency of minor allele-containing genotypes (TT and CT) was much higher in SCCHN patients (51.8%) compared to that in normal controls (30.3%) (p = 0. 0005). When considering a relatively small number of cases (n = 147) and controls (n = 168) in our study, larger studies are needed to validate the genetic effects of XRCC1 polymorphisms in Asian populations. In conclusion, the result from our study provides additional evidence of an association of the XRCC1 polymorphism (Arg194Trp) with SCCHN as markers of genetic susceptibility in the Korean population.