X-Ray Repair Cross-Complementing Group 1 (XRCC1) Genetic Polymorphisms and Gastric Cancer Risk: A HuGE Review and Meta-Analysis

Department of Gastroenterology, Renji Hospital, Shanghai Institute of Gastrointestinal Diseases, School of Medicine, Shanghai Jiaotong University, People’s Republic of China.
American journal of epidemiology (Impact Factor: 4.98). 02/2011; 173(4):363-75. DOI: 10.1093/aje/kwq378
Source: PubMed

ABSTRACT The authors performed a systematic review and meta-analysis of associations of the x-ray repair cross-complementing 1 gene (XRCC1) single nucleotide polymorphisms (SNPs) Arg194Trp, Arg280His, and Arg399Gln with gastric cancer risk, based on eligible studies retrieved from electronic databases for the period January 2000-December 2009. Ultimately, 12, 6, and 3 studies were found to be eligible for meta-analyses of Arg399Gln, Arg194Trp, and Arg280His, respectively. Regrouping was adopted in accordance with the most probably appropriate genetic models. Potential sources of heterogeneity were sought out. For overall gastric cancer, the pooled odds ratios for Arg399Gln, Arg194Trp, and Arg280His were 1.04 (95% confidence interval (CI): 0.90, 1.20; P = 0.572), 0.83 (95% CI: 0.68, 1.01; P = 0.059), and 1.18 (95% CI: 0.92, 1.50; P = 0.194), respectively. After stratification of the Arg399Gln SNP data by anatomic type (cardia vs. noncardia), the pooled odds ratio was 1.07 (95% CI: 0.84, 1.37; P = 0.568). The authors conclude that the 3 SNPs evaluated are not associated with risk of gastric cancer. The Arg399Gln SNP is not associated with the cardia type of gastric cancer. Evidently, the heterogeneity regarding the Arg399Gln SNP across studies is not explained by ethnicity, genotyping technique, sample size, or date of publication.

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Available from: Gang Huang, Aug 13, 2015
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    • "Risk factors of GC identified so far include H. pylori (HP) infection, smoking, alcohol, diet and nutrition such as red and processed meat, genetics and epigenetic factors (Gonzalez et al., 2012). Host genetic susceptibility is assumed to be an important factor for development of GC, and can be partially explained by genetic variations like single nucleotide polymorphisms (SNPs) in susceptible genes (Xue et al., 2011). In addition, gene-gene and geneenvironment interactions may add to the risk of GC in an additive or multiplicative model. "
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    ABSTRACT: Objective: Gastric cancer (GC) is one of the most common malignancies and its mortality ranks third among all cancers in China. We previously noted that XRCC1 Arg194Trp was associated with GC risk in Western China in a study on XRCC1 Arg194Trp and ADPRT Val762Ala. We aimed to further explore the association of these polymorphisms with risk of the noncardia subtype. Methods: We enrolled 176 noncardia GC patients and 308 controls from four hospitals and a community between October 2010 and August 2011. Genotyping was performed in a 384-well plate format on the Sequenom MassARRAY platform. A self-designed questionnaire was utilized to collect epidemiological data from the subjects regarding demographic factors and potential risk factors. Results: Subjects were aged 56.8±11.8 (mean ± standard deviation) and 57.6±11.1 years in the case and control groups, respectively. Individuals carrying the XRCC1 Trp/Trp or Arg/Trp variant genotype were at significantly increased risk of noncardia GC (adjusted OR, 1.48; 95% CI, 1.00-2.17), after adjustment for family history of cancer, drinking, and smoking. The increased risk of XRCC1 Arg194Trp variant genotype was more pronounced among subjects below 60 years old (adjusted OR, 1.78; 95% CI, 1.07-2.96), compared to older individuals. ADPRT Val762Ala variants (Ala/Ala or Val/Ala) were not associated with noncardia GC (adjusted OR, 1.03; 95% CI, 0.69-1.54). Conclusions: Our study suggests that XRCC1 Arg194Trp is a genetic susceptibility factor for developing noncardia GC in Han Chinese in Western China. In particular, individuals with the XRCC1 Arg194Trp variant genotype are at increased risk for GC below 60 years old.
    Asian Pacific journal of cancer prevention: APJCP 11/2012; 13(11):5637-42. DOI:10.7314/APJCP.2012.13.11.5637 · 2.51 Impact Factor
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    • "In this regard, functional variants of XRCC1 and ADPRT may alter BER functions and thus play an essential role in the evolution of gastric lesions (Li et al., 2009). Host genetic susceptibility to carcinogenesis can be partially explained by genetic variations like single nucleotide polymorphisms in susceptible genes (Xue et al., 2011). XRCC1 Arg194Trp (C26304T) and ADPRT Val762Ala (T2446C) are two common candidate single-nucleotide polymorphisms that cause an amino acid change (Li et al., 2009). "
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    ABSTRACT: Gastric cancer remains a major health problem in China. We hypothesized that XRCC1 Arg194Trp and ADPRT Val762Ala may be associated with risk. We designed a multicenter 1:1 matched case- control study of 307 pairs of gastric cancers and controls between October 2010 and August 2011. XRCC1 Arg194Trp and ADPRT Val762Ala were sequenced, and demographic data as well as lifestyle factors were collected using a self-designed questionnaire. Individuals carrying XRCC1 Trp/Trp or Arg/Trp variant genotype had a significantly increased risk of gastric cancer (OR, 1.718; 95% CI, 1.190-2.479), while the OR for ADPRT Val762Ala variant genotype (Ala/Ala or Val/Ala) was 1.175 (95% CI, 0.796-1.737). No gene-gene or gene-environment interactions were found. In addition, family history of cancer and drinkers proportion were higher among cases than among controls (P<0.05). XRCC1 194 Arg/Trp or Trp/Trp genotype, family history of cancer, and drinking are suspected risk factors of gastric cancer from our study. Our findings may offer insight into further similar large gene-environment and gene-gene studies in this region.
    Asian Pacific journal of cancer prevention: APJCP 05/2012; 13(5):2139-44. DOI:10.7314/APJCP.2012.13.5.2139 · 2.51 Impact Factor
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    • "These are: -77T>C (promoter, rs3213245), Arg194Trp (R194W, rs1799782), Arg280His (R280H, rs25489) and Arg399Gln (R399Q, rs25487). The three polymorphisms found in the coding region, R194W, R280H and R399Q, have been analysed in meta-studies for different cancer types, but so far the meta-studies have failed to provide an unambiguous relationship between the polymorphism and disease prevalence [27] [28] [29] [30]. This could partly be a result of population dependent differences in the frequency and distribution of the SNPs, e.g. the R280H variant is more frequent in Asians (7-15%) than in Caucasians (4-9%). "
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    ABSTRACT: XRCC1 functions as a non-enzymatic, scaffold protein in single strand break repair (SSBR) and base excision repair (BER). Here, we examine different regions of XRCC1 for their contribution to the scaffolding functions of the protein. We found that the central BRCT1 domain is essential for recruitment of XRCC1 to sites of DNA damage and DNA replication. Also, we found that ectopic expression of the region from residue 166-436 partially rescued the methyl methanesulfonate (MMS) hypersensitivity of XRCC1-deficient EM9 cells, suggesting a key role for this region in mediating DNA repair. The three most common amino acid variants of XRCC1, Arg194Trp, Arg280His and Arg399Gln, are located within the region comprising the NLS and BRCT1 domains, and these variants may be associated with increased incidence of specific types of cancer. While we could not detect differences in the intra-nuclear localization or the ability to support recruitment of POLβ or PNKP to micro-irradiated sites for these variants relative to the conservative protein, we did observe lower foci intensity after micro-irradiation and a reduced stability of the foci with the Arg280His and Arg399Gln variants, respectively. Furthermore, when challenged with MMS or hydrogen peroxide, we detected small but consistent differences in the repair profiles of cells expressing these two variants in comparison to the conservative protein.
    DNA repair 01/2012; 11(4):357-66. DOI:10.1016/j.dnarep.2012.01.001 · 3.36 Impact Factor
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