Abstract
The X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair. Several polymorphisms in the XRCC1 gene have been described, including Arg399Gln. Previous studies investigating the association between genetic polymorphism of Arg399Gln XRCC1 and risk of breast cancer have provided inconsistent results. A meta-analysis was conducted to investigate the association between common genetic variant in the XRCC1 gene (exon 10, Arg399Gln) with breast cancer risk. We identified 36 eligible studies, in relation to the Arg399Gln polymorphism of XRCC1 and risk of breast cancer. These studies comprised of 43,716 subjects (20,837 patients and 22,879 controls). We first estimated the risk of the genotypes Arg/Gln and Gln/Gln compared with the wild-type Arg/Arg homozygote, and then evaluated the risk of Gln/Gln versus (Arg/Gln+Arg/Arg) and (Gln/Gln+Arg/Gln) versus Arg/Arg, which assumed recessive and dominant effects, respectively, of the variant 399Gln allele. There was significant heterogeneity between studies. The overall ORs showed that the breast cancer risk were not associated with the XRCC1 genotypes. The heterogeneity between studies decreased dramatically when studies stratified into Asian and Western countries. There was significant association between the polymorphism of XRCC1 and breast cancer risk among studies of Asian countries. In Asian countries the Arg/Gln versus Arg/Arg (OR = 0.98, 95% CI: 0.88–1.10) and Gln/Gln+Arg/Gln versus Arg/Arg (OR = 1.05, 95% CI: 0.95–1.18) were not associated with increased risk of breast cancer. On the other hand, both Gln/Gln versus Arg/Arg (OR = 1.46, 95% CI: 1.19–1.79) and Gln/Gln versus Arg/Gln+Arg/Arg (OR = 1.49, 95% CI: 1.22–1.81) increased the risk. Therefore, it could be concluded that 399Gln allele might act as a recessive allele in its association with breast cancer risk.
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References
Hung RJ, Hall J, Bernnan P, Boffestta P (2005) Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. Am J Epidemiol 162:925–942
Cardecott KW (2003) XRCC1 and DNA stand break repair. DNA Repair (Amst) 2:955–969
Thompson LH, Bachinski LL, Stallings RL, Dolf G, Weber CA, Westerveld A, Siciliano MJ (1989) Complementation of repair gene mutations on the hemizygous chromosome 9 in CHO: a third repair gene on human chromosome 19. Genomics 5:670–679
Thompson LH, West MG (2000) XRCC1 keeps DNA from getting stranded. Mutat Res 459:1–18
Trask B, Fertitta A, Christensen M, Youngblom J, Bergmann A, Copeland A, de Jong P, Mohrenweiser H, Olsen A, Carrano A, Tynan K (1993) Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers. Genomics 15:133–145
Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW (2001) XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell 104:107–117
Tebbes RS, Flannery ML, Meneses JJ, Hartmann A, Tucker JD, Thompson LH, Cleaver JE, Pedersen RA (1999) Requirement for the Xrcc1 DNA base excision repair gene during early mouse development. Dev Biol 208:513–529
Tebbes RS, Thompson LH, Cleaver JE (2003) Rescue of Xrcc1 knockout mouse embryo lethality by trans gene-complementation. DNA Repair (Amst) 2:1405–1417
Goode EL, Ulrich CM, Potter JD (2002) Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev 11:1513–1530
Hu Z, Ma H, Chen F, Wei Q, Shen H (2005) XRCC1 polymorphisms and cancer risk: a meta-analysis of 38 case–control studies. Cancer Epidemiol Biomarkers Prev 14:1810–1818
Duell EJ, Wiencke JK, Cheng TJ, Varkonvi A, Zuo ZF, Ashok TD, Mark EJ, Wain JC, Christiani DC, Kelse KT (2000) Polymorphisms in the DNA repair gene XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis 21:965–971
Lei YC, Hwang SJ, Chang CC, Kuo HW, Luo JC, Chang MJW, Cheng TJ (2002) Effects on sister chromatid exchange frequency of polymorphisms in DNA repair gene XRCC1 in smokers. Mutat Res 519:93–101
Matullo G, Palli D, Peluso M, Guarrera S, Carturan S, Celentano E, Krogh V, Munnia A, Tumino R, Polidoro S, Piazza A, Vineis P (2001) XRCC1, XRCC3, XPD gene polymorphisms, smoking and 32P-DNA adducts in a sample of healthy subjects. Carcinogenesis 22:1437–1445
Relton CL, Daniel CP, Fisher A, Chase DS, Burn J, Tawn EJ (2002) Polymorphisms of the DNA repair gene XRCC1 and the frequency of somatic mutations of the glycophorin A locus in newborns. Mutat Res 502:61–68
Wang Y, Spitz MR, Zhu Y, Dang Q, Shete S, Wu X (2003) From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity. DNA Repair (Amst) 2:901–908
Lunn RM, Langlois RG, Hsieh LL, Thompson CL, Bell DA (1999) XRCC1 polymorphisms: effects on aftatoxin B DNA adducts and glycophorin A variant frequency. Cancer Res 59:2557–2561
Abdel-Rahman SZ, El-Zein RA (2000) The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by tobacco-specific nitrosamine NNK. Cancer Lett 159:63–71
Hu JJ, Smith TR, Miller MS, Mohrenweiser HW, Golden A, Case LD (2001) Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity. Carcinogenesis 22:917–922
Qu T, Morii E, Oboki K, Lu Y, Morimoto K (2005) Micronuclei in EM9 cells expressing polymorphic forms of human XRCC1. Cancer Lett 221:91–95
Qu T, Morimoto K (2005) X-ray repair cross-complementing group 1 polymorphisms and cancer risks in Asian populations: a mini review. Cancer Detect Prev 29:215–220
Duell EJ, Millikan RC, Pittman GS, Winkel S, Lunn RM, Tse CK, Eaton A, Mohrenweiser HW, Newman B, Bell DA (2001) Polymorphisms in the DNA repair gene XRCC1 and breast cancer. Cancer Epidemiol Biomarkers Prev 10:217–222
Kim SU, Park SK, Yoo KY, Yoon KS, Choi JY, Seo JS, Park WY, Kim JH, Noh DY, Ahn SH, Choe KJ, Strickland PT, Hirvonen A, Kang D (2002) XRCC1 genetic polymorphism and breast cancer risk. Pharmacogenetics 12:335–338
Smith TR, Levine EA, Perrier ND, Miller MS, Freimanis RI, Lohman K, Case LD, Xu J, Mohrenweiser HW, Hu JJ (2003) DNA-repair genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 12:1200–1204
Shu XO, Cai Q, Gao YT, Wen W, Jin F, Zheng W (2003) A population-based case–control study of the Arg399Gln polymorphism in DNA repair gene XRCC1 and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 12:1462–1467
Smith TR, Miller MS, Lohman K, Lange EM, Case LD, Mohrenweiser HW, Hu JJ (2003) Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer. Cancer Lett 190:183–190
Moullan N, Cox DG, Angele S, Romestaing P, Gerard JP, Hall J (2003) Polymorphisms in the DNA repair gene XRCC1, breast cancer risk, and response to radiotherapy. Cancer Epidemiol Biomarkers Prev 12:1168–1174
Han J, Hankinson SE, De Vivo I, Spiegelman D, Tamimi RM, Mohrenweiser HW, Colditz GA, Hunter DJ (2003) A prospective study of XRCC1 haplotypes and their interaction with plasma carotenoids on breast cancer risk. Cancer Res 63:8336–8341
Figueiredo JC, Knight JA, Briollais L, Andrulis IL, Ozcelik H (2004) Polymorphisms XRCC1-R399Q and XRCC3-T241M and the risk of breast cancer at the Ontario site of the breast cancer family registry. Cancer Epidemiol Biomarkers Prev 13:583–591
Försti A, Angelini S, Festa F, Sanyal S, Zhang Z, Grzybowska E, Pamula J, Pekala W, Zientek H, Hemminki K, Kumar R (2004) Single nucleotide polymorphisms in breast cancer. Oncol Rep 11:917–922
Deligezer U, Dalay N (2004) Association of the XRCC1 gene polymorphisms with cancer risk in Turkish breast cancer patients. Exp Mol Med 36:572–575
Dufloth RM, Costa S, Schmitt F, Zeferino LC (2005) DNA repair gene polymorphisms and susceptibility to familial breast cancer in a group of patients from Campinas, Brazil. Genet Mol Res 4:771–782
Shen J, Gammon MD, Terry MB, Wang L, Wang Q, Zhang F, Teitelbaum SL, Eng SM, Sagiv SK, Gaudet MM, Neugut AI, Santella RM (2005) Polymorphisms in XRCC1 modify the association between polycyclic aromatic hydrocarbon-DNA adducts, cigarette smoking, dietary antioxidants, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 14:336–342
Chacko P, Rajan B, Joseph T, Mathew BS, Pillai MR (2005) Polymorphisms in DNA repair gene XRCC1 and increased genetic susceptibility to breast cancer. Breast Cancer Res Treat 89:15–21
Patel AV, Calle EE, Pavluck AL, Feigelson HS, Thun MJ, Rodriguez C (2005) A prospective study of XRCC1 (X-ray cross-complementing group 1) polymorphisms and breast cancer risk. Breast Cancer Res 7:R1168–R1173
Metsola K, Kataja V, Sillanpää P, Siivola P, Heikinheimo L, Eskelinen M, Kosma VM, Uusitupa M, Hirvonen A (2005) XRCC1 and XPD genetic polymorphisms, smoking and breast cancer risk in a Finnish case–control study. Breast Cancer Res 7:R987–R997
Breast Cancer Association Consortium (2006) Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J Natl Cancer Inst 98:1382–1396
Zhang Y, Newcomb PA, Egan KM, Titus-Ernstoff L, Chanock S, Welch R, Brinton LA, Lissowska J, Bardin-Mikolajczak A, Peplonska B, Szeszenia Dabrowska N, Zatonski W, Garcia-Closas M (2006) Genetic polymorphisms in base-excision repair pathway genes and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 15:353–358
Brewster AM, Jorgensen TJ, Ruczinski I, Huang HY, Hoffman S, Thuita L, Newschaffer C, Lunn RM, Bell D, Helzlsouer KJ (2006) Polymorphisms of the DNA repair genes XPD (Lys751Gln) and XRCC1 (Arg399Gln and Arg194Trp): relationship to breast cancer risk and familial predisposition to breast cancer. Breast Cancer Res Treat 95:73–80
Zhai X, Liu J, Hu Z, Wang S, Qing J, Wang X, Jin G, Gao J, Wang X, Shen H (2006) Polymorphisms of ADPRT Val762Ala and XRCC1 Arg399Gln and risk of breast cancer in Chinese women: a case control analysis. Oncol Rep 15:247–252
Thyagarajan B, Anderson KE, Folsom AR, Jacobs DR Jr, Lynch CF, Bargaje A, Khaliq W, Gross MD (2006) No association between XRCC1 and XRCC3 gene polymorphisms and breast cancer risk: Iowa women’s health study. Cancer Detect Prev 30:313–321
Bu D, Tomlinson G, Lewis CM, Zhang C, Kildebeck E, Euhus DM (2006) An intronic polymorphism associated with increased XRCC1 expression, reduced apoptosis and familial breast cancer. Breast Cancer Res Treat 99:257–265
Kohan L, Omidvari S, Saadat M (2006) Combination of XRCC1, GSTM1, and GSTM1 genetic polymorphisms and susceptibility to male breast cancer. Int J Cancer Res 2:415–419
Costa S, Pinto D, Pereira D, Rodrigues H, Cameselle-Teijeiro J, Medeiros R, Schmitt F (2007) DNA repair polymorphisms might contribute differentially on familial and sporadic breast cancer susceptibility: a study on a Portuguese population. Breast Cancer Res Treat 103:209–217
Jin MJ, Chen K, Zhang SS, Zhang YJ, Ren YJ, Xu H, Yao KY, Li QL, Ma XY (2006) Association of single nucleotide polymorphisms and haplotypes in DNA repair gene XRCC1 with susceptibility of breast cancer. Zhejiang Da Xue Xue Bao Yi Xue Ban 35:370–376 (Chinese)
Silva SN, Moita R, Azevedo AP, Gouveia R, Manita I, Pina JE, Rueff J, Gaspar J (2007) Menopausal age and XRCC1 gene polymorphisms: role in breast cancer risk. Cancer Detect Prev 31:303–309
Saadat M, Kohan L, Omidvari S (2008) Genetic polymorphisms of XRCC1 (codon 399) and susceptibility to breast cancer in Iranian women, a case–control study. Breast Cancer Res Treat (Epub ahead of print). doi:10.1007/s10549-007-9811-5
Loizidou MA, Michael T, Neuhausen SL, Newbold RF, Marcou Y, Kakouri E, Daniel M, Papadopoulos P, Malas S, Kyriacou K, Hadjisavvas A (2008) Genetic polymorphisms in the DNA repair genes XRCC1, XRCC2 and XRCC3 and risk of breast cancer in Cyprus. Breast Cancer Res Treat (Epub ahead of print). doi:10.1007/s10549-007-9881-4
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748
Mohamadynejad P, Saadat M (2008) Genetic polymorphisms of XRCC1 (at codons 194 and 399) in Shiraz population (Fars province, southern Iran). Mol Biol Rep (Epub ahead of print). doi:10.1007/s1033-007-9138-7
Kiyohara C, Takayama K, Nakanishi Y (2006) Association of genetic polymorphisms in the base excision repair pathway with lung cancer risk: a meta-analysis. Lung Cancer 54:267–283
Saadat M (2006) Genetic polymorphisms of glutathione S-transferase T1 (GSTT1) and susceptibility to gastric cancer: a meta-analysis. Cancer Sci 97:505–509
Taylor RM, Thistlethwaite A, Caldecott KW (2002) Central role for the XRCC1 BRCT-I domain in mammalian DNA single-strand break repair. Mol Cell Biol 22:2556–2563
Liede A, Narod SA (2002) Hereditary breast and ovarian cancer in Asia: genetic epidemiology of BRCA1, and BRCA2. Hum Mutat 20:413–424
Levy-Lahad E, Lahad A, Eisenberg S, Dagan E, Paperna T, Kasinetz L, Catane R, Kaufman B, Beller U, Renbaum P, Gershoni-Baruch R (2001) A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc Natl Acad Sci USA 98:3232–3236
Wang WW, Spurdle AB, Kolachana P, Bove B, Modan B, Ebbers SM, Suthers G, Tucker MA, Kaufman DJ, Doody MM, Tarone RE, Daly M, Levavi H, Pierce H, Chetrit A, Yechezkel GH, Chenevix-Trench G, Offit K, Godwin AK, Struewing JP (2001) A single nucleotide polymorphism in the 5′ untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 10:955–960
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The authors are indebted to Dr. Hassan Mohabatkar for critical reading of the manuscript and for his contribution in discussion. This study was supported by Shiraz University.
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Saadat, M., Ansari-Lari, M. Polymorphism of XRCC1 (at codon 399) and susceptibility to breast cancer, a meta-analysis of the literatures. Breast Cancer Res Treat 115, 137–144 (2009). https://doi.org/10.1007/s10549-008-0051-0
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DOI: https://doi.org/10.1007/s10549-008-0051-0