An Updated Meta-analysis on the Association of X-Ray Repair Cross Complementing Group 1 Codon 399 Polymorphism with Hepatocellular Carcinoma Risk

  • Wang, Ya-Dong (Henan Center for Disease Control and Prevention, First Affiliated Hospital of Zhengzhou University) ;
  • Zhai, Wen-Long (Department of General Surgery, First Affiliated Hospital of Zhengzhou University) ;
  • Wang, Hai-Yu (Henan Center for Disease Control and Prevention, First Affiliated Hospital of Zhengzhou University) ;
  • Xia, Xiang-Qun (Henan Center for Disease Control and Prevention, First Affiliated Hospital of Zhengzhou University)
  • Published : 2014.06.15


Background: A number of studies have reported the association of X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism with susceptibility to hepatocellular carcinoma (HCC). However, the results were inconsistent and inconclusive. The aim of this study was to comprehensively explore the association of XRCC1 Arg399Gln variant with HCC risk. Materials and Methods: Systematic searches of PubMed, Elsevier, Science Direct, CNKI and Chinese Biomedical Literature Database were performed. Pooled odds ratio (OR) with 95% confidence intervals (CI) was calculated to estimate the strength of association. Results: Overall, we observed an increased HCC risk among subjects carrying XRCC1 codon 399 Gln/Gln, Arg/Gln and Gln/Gln+Arg/Gln genotypes (OR=1.20, 95%CI: 1.05-1.38, OR=1.16, 95%CI: 1.05-1.28, and OR=1.14, 95%CI: 1.04-1.24, respectively) based on 20 studies including 3374 cases and 4633 controls. In subgroup analysis, we observed an increased risk of XRCC1 codon 399 Gln/Gln, Arg/Gln and Gln/Gln+Arg/Gln polymorphisms for HCC in hospital-based study (OR=1.25, 95%CI: 1.03-1.51, OR=1.21, 95%CI: 1.07-1.36 and OR=1.18, 95%CI: 1.06-1.31, respectively) and in Asian population (OR=1.19, 95%CI: 1.03-1.38, OR=1.17, 95%CI: 1.04-1.30 and OR=1.14, 95%CI: 1.04-1.25, respectively). Limiting the analysis to the studies with controls in agreement with Hardy-Weinberg equilibrium (HWE), we observed an increased HCC risk among Gln/Gln, Arg/Gln and Gln/ Gln+Arg/Gln genotype carriers (OR=1.17, 95%CI: 1.05-1.29, OR=1.12, 95%CI: 1.00-1.25 and OR=1.11, 95%CI: 1.02-1.21, respectively). Conclusions: This updated meta-analysis results suggest that XRCC1 Arg399Gln variants may contribute to HCC risk. Well-designed studies with larger sample size were required to further verify our findings.


Supported by : National Natural Science Foundation of China


  1. Bose S, Tripathi DM, Sukriti, et al (2013). Genetic polymorphisms of CYP2E1 and DNA repair genes HOGG1 and XRCC1: Association with hepatitis B related advanced liver disease and cancer. Gene, 519, 231-7.
  2. Begg CB, Mazumdar M (1994). Operating characteristics of a rank correlation test for publication bias. Biometrics, 50, 1088-101.
  3. Bo W, Zhang G, Li D, Wang X (2012). The polymorphisms of XRCC1 gene and susceptibility to pulmonary cancer. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi, 22, 45-8 (in Chinese).
  4. Borentain P, Gerolami V, Ananian P, et al (2007). DNA-repair and carcinogen-metabolising enzymes genetic polymorphisms as an independent risk factor for hepatocellular carcinoma in Caucasian liver-transplanted patients. Eur J Cancer, 43, 2479-86.
  5. Chen B, Long X, Fu G (2011). Meta-analysis of XRCC1 Codon 399 polymorphism and susceptibility to hepatocellular carcinoma. J Shanghai Jiaotong Univ (Medical Science), 31, 1588-91 (in Chinese).
  6. Chen CC, Yang SY, Liu CJ, et al (2005). Association of cytokine and DNA repair gene polymorphisms with hepatitis B-related hepatocellular carcinoma. Int J Epidemiol, 34, 1310-8.
  7. Clifford RJ, Zhang J, Meerzaman DM, et al (2010). Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma. Hepatology, 52, 2034-43.
  8. DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Control Clin Trials, 7, 177-88.
  9. Egger M, Davey Smith G, Schneider M, et al (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315, 629-34.
  10. Dominguez-Malagon H, Gaytan-Graham S (2001). Hepatocellular carcinoma: an update. Ultrastruct Pathol, 25, 497-516.
  11. Duan WH, Zhu ZY, Liu JG, et al (2012). XRCC1 Arg399Gln gene polymorphism and hepatocellular carcinoma risk in the Chinese Han population: a meta-analysis. Asian Pac J Cancer Prev, 13, 3601-4.
  12. Duell EJ, Wiencke JK, Cheng TJ, et al (2000). Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis, 21, 965-71.
  13. Gulnaz A, Sayyed AH, Amin F, et al (2013). Association of XRCC1, XRCC3, and XPD genetic polymorphism with an increased risk of hepatocellular carcinoma because of the hepatitis B and C virus. Eur J Gastroenterol Hepatol, 25, 166-79.
  14. Guo LY, Jin XP, Niu W, et al (2012). Association of XPD and XRCC1 genetic polymorphisms with hepatocellular carcinoma risk. Asian Pac J Cancer Prev, 13, 4423-6.
  15. Han X, Xing Q, Li Y, et al (2012). Study on the DNA repair gene XRCC1 and XRCC3 polymorphism in prediction and prognosis of hepatocellular carcinoma risk. Hepatogastroenterology, 59, 2285-9.
  16. He G, Huang T, Deng W, et al (2012). Research on Association Between XRCC1Arg399Gln Polymorphism and Liver Cancer. J Guangxi University of Chinese Medicine, 15, 1-3.
  17. Huang MD, Chen XF, Xu G, et al (2012). Genetic variation in the NBS1 gene is associated with hepatic cancer risk in a Chinese population. DNA Cell Biol, 31, 678-82.
  18. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.
  19. Li J, Li Z, Feng L, Guo W, Zhang S (2013). Polymorphisms of DNA repair gene XRCC1 and hepatocellular carcinoma risk among East Asians: a meta-analysis. Tumour Biol, 34, 261-9.
  20. Jia Z, Su H, Li X, et al (2010). Polymorphisms of UGTIA7 and XRCCI are associated with an increased risk of hepatocellular carcinoma in Northeast China. Chin J Cancer Res, 22, 260-6.
  21. Kiran M, Saxena R, Chawla YK, et al (2009). Polymorphism of DNA repair gene XRCC1 and hepatitis-related hepatocellular carcinoma risk in Indian population. Mol Cell Biochem, 327, 7-13.
  22. Kirk GD, Turner PC, Gong Y, et al (2005). Hepatocellular carcinoma and polymorphisms in carcinogen-metabolizing and DNA repair enzymes in a population with aflatoxin exposure and hepatitis B virus endemicity. Cancer Epidemiol Biomarkers Prev, 14, 373-9.
  23. Liu F, Li B, Wei Y, et al (2011). XRCC1 genetic polymorphism Arg399Gln and hepatocellular carcinoma risk: a meta-analysis. Liver Int, 31, 802-9.
  24. Liu S, Li L, Ma J (2012). Association analysis of XRCC1 genetic polymorphism loci with primary heptocellular carcinoma in chinese population. Prog Anatomical Sciences, 18, 147-50.
  25. Long XD, Ma Y, Wei YP, Deng ZL (2004). Polymorphism of dna repair gene xrcc1 and risk of hepatocellular carcinoma. Journal of Guangxi Medical University, 21, 313-5.
  26. Long XD, Ma Y, Wei YP, Deng ZL (2006). The polymorphisms of GSTM1, GSTT1, HYL1*2, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China. Hepatol Res, 36, 48-55.
  27. Long XD, Yao JG, Huang YZ, et al (2011). DNA repair gene XRCC7 polymorphisms (rs#7003908 and rs#10109984) and hepatocellular carcinoma related to AFB1 exposure among Guangxi population, China. Hepatol Res, 41, 1085-93.
  28. Pan Y, Zhao L, Chen XM, et al (2013). The XRCC1 Arg399Gln genetic polymorphism contributes to hepatocellular carcinoma susceptibility: an updated meta- analysis. Asian Pac J Cancer Prev, 14, 5761-7.
  29. Lunn RM, Langlois RG, Hsieh LL, et al (1999). XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. Cancer Res, 59, 2557-61.
  30. Mohana Devi S, Balachandar V, Arun M, et al (2013). Analysis of Genetic Damage and Gene Polymorphism in Hepatocellular Carcinoma (HCC) Patients in a South Indian Population. Dig Dis Sci, 58, 759-67.
  31. Pan HZ, Liang J, Yu Z, et al (2011). Polymorphism of DNA repair gene XRCC1 and hepatocellular carcinoma risk in Chinese population. Asian Pac J Cancer Prev, 12, 2947-50.
  32. Pang RW, Joh JW, Johnson PJ, et al (2008). Biology of hepatocellular carcinoma. Ann Surg Oncol, 15, 962-71.
  33. Ren Y, Wang D, Li Z, et al (2008). Study on the relationship between gene XRCC1 codon 399 single nucleotide polymorphisms and primary hepatic carcinoma in Han nationality. Chinese J Clinical Hepatology, 24, 361-4.
  34. Salanti G, Amountza G, Ntzani EE, et al (2005). Hardy-Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. Eur J Hum Genet, 13, 840-8.
  35. Shen MR, Jones IM, Mohrenweiser H (1998). Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. Cancer Res, 58, 604-8.
  36. Tang Y, Li X, Liu T, et al (2011). Genetic polymorphisms of DNA repair genes in patients with hepatocellular carcinoma. Shandong Medical J, 51, 19-20.
  37. Xie T, Wang ZG, Zhang JL, et al (2012). X-ray repair cross-complementing group 1 polymorphisms and hepatocellular carcinoma: a meta-analysis. World J Gastroenterol, 18, 4207-14.
  38. Vidal AE, Boiteux S, Hickson ID, et al (2001). XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein-protein interactions. EMBO J, 20, 6530-9.
  39. Wang W, Dang S, Li Y, et al (2013). hOGG1 Ser326Cys Polymorphism and Risk of Hepatocellular Carcinoma among East Asians: A Meta-Analysis. PLoS One, 8, 60178.
  40. Wu H (2009). Correlation between DNA repair gene XRCC1 single nucleotide polymorphism and susceptibility to hepatocellular carcinoma in Fusui County of Guangxi, 2009 (article in Chinese). Available at aspx?dbname=CMFD2009&filename=2009132690.nh (accessed 10 March 2011).
  41. Yang J, Han Y, Zheng S (2004). Influence of human XRCC1-399 single nucleotide polymorphism on primary hepatocytic carcinoma. Tumor, 24, 322-4.
  42. Yin J, Vogel U, Ma Y, et al (2007). The DNA repair gene XRCC1 and genetic susceptibility of lung cancer in a northeastern Chinese population. Lung Cancer, 56, 153-60.
  43. Yu MW, Yang SY, Pan IJ, et al (2003). Polymorphisms in XRCC1 and glutathione S-transferase genes and hepatitis B-related hepatocellular carcinoma. J Natl Cancer Inst, 95, 1485-8.
  44. Zeng X, Yu H, Qiu X, et al (2010). A case-control study of polymorphismof XRCC1 gene and the risk of hepatocellular carcinoma. Chin J Dis Control Prev, 14, 760-3.
  45. Zeng XY, Huang JM, Xu JW, et al (2013). Meta-analysis demonstrates lack of a relationship between XRCC1-399 gene polymorphisms and susceptibility to hepatocellular carcinoma. Genet Mol Res, 12, 1916-23.
  46. Zhang H, Wang P, Dai L, et al (2010). Meta-analysis of the relationship between polymorphisms of 399 point of X-ray repair cross complementing gene group 1 and hepatocellular carcinoma. Wei Sheng Yan Jiu, 39, 664-8.
  47. Zhang Y, Newcomb PA, Egan KM, et al (2006). Genetic polymorphisms in base-excision repair pathway genes and risk of breast cancer. Cancer Epidemiol Biomarkers Prev, 15, 353-8.
  48. Zienolddiny S, Campa D, Lind H, et al (2006). Polymorphisms of DNA repair genes and risk of non-small cell lung cancer. Carcinogenesis, 27, 560-7.

Cited by

  1. Independent and Additive Interaction Between Tumor Necrosis Factor β +252 Polymorphisms and Chronic Hepatitis B and C Virus Infection on Risk and Prognosis of Hepatocellular Carcinoma: a Case-Control Study vol.15, pp.23, 2015,
  2. The Relationship Between Single-Nucleotide Polymorphisms, the Expression of DNA Damage Response Genes, and Hepatocellular Carcinoma in a Polish Population vol.36, pp.8, 2017,
  3. Arg399Gln Gene Polymorphism and Hepatocellular Carcinoma Risk in the Italian Population vol.32, pp.2, 2017,