Genetic polymorphisms of DNA double-strand break repair pathway genes and glioma susceptibility

BMC Cancer

Yongping You²  Tao Jiang¹  Chunsheng Kang³  Wei Yan¹  Lin Zhao²  Peng Zou²  Peng Zhao² 

[1]Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing, 100050, China

[2]Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

[3]Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China

关键词: Susceptibility;    Glioma;    Single nucleotide polymorphisms (SNPs);    DNA double-strand breaks (DSBs);   

Others  :  1079757
DOI  :  10.1186/1471-2407-13-234

 received in 2013-01-01, accepted in 2013-05-03,  发布年份 2013

【 摘 要 】

Background

Genetic variations in DNA double-strand break repair genes can influence the ability of a cell to repair damaged DNA and alter an individual’s susceptibility to cancer. We studied whether polymorphisms in DNA double-strand break repair genes are associated with an increased risk of glioma development.

Methods

We genotyped 10 potentially functional single nucleotide polymorphisms (SNPs) in 7 DNA double-strand break repair pathway genes (XRCC3, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in a case–control study including 384 glioma patients and 384 cancer-free controls in a Chinese Han population. Genotypes were determined using the OpenArray platform.

Results

In the single-locus analysis there was a significant association between gliomas and the LIG4 rs1805388 (Ex2 +54C>T, Thr9Ile) TT genotype (adjusted OR, 3.27; 95% CI, 1.87-5.71), as well as the TC genotype (adjusted OR, 1.62; 95% CI, 1.20-2.18). We also found that the homozygous variant genotype (GG) of XRCC4 rs1805377 (IVS7-1A>G, splice-site) was associated with a significantly increased risk of gliomas (OR, 1.77; 95% CI, 1.12-2.80). Interestingly, we detected a significant additive and multiplicative interaction effect between the LIG4 rs1805388 and XRCC4 rs1805377 polymorphisms with an increasing risk of gliomas. When we stratified our analysis by smoking status, LIG4 rs1805388 was associated with an increased glioma risk among smokers.

Conclusions

These results indicate for the first time that LIG4 rs1805388 and XRCC4 rs1805377, alone or in combination, are associated with a risk of gliomas.

【 授权许可】

   
2013 Zhao et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Xue QC, Pu PY, Yang YS, Shen CH: A survey of 790 cases of astrocytoma. Clin Neurol Neurosurg 1990, 92(1):27-33.
• [2]Ohgaki H, Kleihues P: Epidemiology and etiology of gliomas. Acta Neuropathol 2005, 109(1):93-108.
• [3]Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007, 114(2):97-109.
• [4]Liu Y, Shete S, Hosking FJ, Robertson LB, Bondy ML, Houlston RS: New insights into susceptibility to glioma. Arch Neurol 2010, 67(3):275-278.
• [5]Soulas-Sprauel P, Rivera-Munoz P, Malivert L, Le Guyader G, Abramowski V, Revy P, de Villartay JP: V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining. Oncogene 2007, 26(56):7780-7791.
• [6]Khanna KK, Jackson SP: DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 2001, 27(3):247-254.
• [7]Recuero-Checa MA, Dore AS, Arias-Palomo E, Rivera-Calzada A, Scheres SH, Maman JD, Pearl LH, Llorca O: Electron microscopy of Xrcc4 and the DNA ligase IV-Xrcc4 DNA repair complex. DNA Repair (Amst) 2009, 8(12):1380-1389.
• [8]Falck J, Coates J, Jackson SP: Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 2005, 434(7033):605-611.
• [9]Stracker TH, Petrini JH: The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol 2011, 12(2):90-103.
• [10]Lieber MR: The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 2010, 79:181-211.
• [11]San Filippo J, Sung P, Klein H: Mechanism of eukaryotic homologous recombination. Annu Rev Biochem 2008, 77:229-257.
• [12]Liu Y, Shete S, Etzel CJ, Scheurer M, Alexiou G, Armstrong G, Tsavachidis S, Liang FW, Gilbert M, Aldape K, Armstrong T, Houlston R, Hosking F, Robertson L, Xiao Y, Wiencke J, Wrensch M, Andersson U, Melin BS, Bondy M: Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 genes involved in the double-strand break repair pathway predict glioblastoma survival. J Clin Oncol 2010, 28(14):2467-2474.
• [13]Liu Y, Shete S, Wang LE, El-Zein R, Etzel CJ, Liang FW, Armstrong G, Tsavachidis S, Gilbert MR, Aldape KD, Xing J, Wu X, Wei Q, Bondy ML: Gamma-radiation sensitivity and polymorphisms in RAD51L1 modulate glioma risk. Carcinogenesis 2010, 31(10):1762-1769.
• [14]Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B (Methodological) 1995, 289-300.
• [15]Grawunder U, Zimmer D, Leiber MR: DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains. Curr Biol 1998, 8(15):873-876.
• [16]Girard PM, Kysela B, Harer CJ, Doherty AJ, Jeggo PA: Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms. Hum Mol Genet 2004, 13(20):2369-2376.
• [17]O’Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer SE, Seidel J, Gatti RA, Varon R, Oettinger MA, Neitzel H, Jeggo PA, Concannon P: DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 2001, 8(6):1175-1185.
• [18]Dore AS, Furnham N, Davies OR, Sibanda BL, Chirgadze DY, Jackson SP, Pellegrini L, Blundell TL: Structure of an Xrcc4-DNA ligase IV yeast ortholog complex reveals a novel BRCT interaction mode. DNA Repair (Amst) 2006, 5(3):362-368.
• [19]Yurchenko V, Xue Z, Sadofsky MJ: SUMO modification of human XRCC4 regulates its localization and function in DNA double-strand break repair. Mol Cell Biol 2006, 26(5):1786-1794.
• [20]Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL, Pellegrini L: Crystal structure of an Xrcc4-DNA ligase IV complex. Nat Struct Biol 2001, 8(12):1015-1019.
• [21]Wu PY, Frit P, Meesala S, Dauvillier S, Modesti M, Andres SN, Huang Y, Sekiguchi J, Calsou P, Salles B, Junop MS: Structural and functional interaction between the human DNA repair proteins DNA ligase IV and XRCC4. Mol Cell Biol 2009, 29(11):3163-3172.
• [22]Tseng RC, Hsieh FJ, Shih CM, Hsu HS, Chen CY, Wang YC: Lung cancer susceptibility and prognosis associated with polymorphisms in the nonhomologous end-joining pathway genes: a multiple genotype-phenotype study. Cancer 2009, 115(13):2939-2948.
• [23]Abe T, Ishiai M, Hosono Y, Yoshimura A, Tada S, Adachi N, Koyama H, Takata M, Takeda S, Enomoto T, Seki M: KU70/80, DNA-PKcs, and Artemis are essential for the rapid induction of apoptosis after massive DSB formation. Cell Signal 2008, 20(11):1978-1985.
• [24]Mahaney BL, Meek K, Lees-Miller SP: Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochem J 2009, 417(3):639-650.
• [25]Frank KM, Sekiguchi JM, Seidl KJ, Swat W, Rathbun GA, Cheng HL, Davidson L, Kangaloo L, Alt FW: Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 1998, 396(6707):173-177.
• [26]Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y, Seidl KJ, Sekiguchi JM, Rathbun GA, Swat W, Wang J, Bronson RT, Malynn BA, Bryans M, Zhu C, Chaudhuri J, Davidson L, Ferrini R, Stamato T, Orkin SH, Greenberg ME, Alt FW: A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 1998, 95(7):891-902.
• [27]Kesari S, Advani SJ, Lawson JD, Kahle KT, Ng K, Carter B, Chen CC: DNA damage response and repair: insights into strategies for radiation sensitization of gliomas. Future Oncol 2011, 7(11):1335-1346.
• [28]Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, Frank KM, Chaudhuri J, Horner J, DePinho RA, Alt FW: Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 2000, 404(6780):897-900.
• [29]Frank KM, Sharpless NE, Gao Y, Sekiguchi JM, Ferguson DO, Zhu C, Manis JP, Horner J, DePinho RA, Alt FW: DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell 2000, 5(6):993-1002.
• [30]Nijnik A, Dawson S, Crockford TL, Woodbine L, Visetnoi S, Bennett S, Jones M, Turner GD, Jeggo PA, Goodnow CC, Cornall RJ: Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome. J Clin Invest 2009, 119(6):1696-1705.
• [31]Sharpless NE, Ferguson DO, O’Hagan RC, Castrillon DH, Lee C, Farazi PA, Alson S, Fleming J, Morton CC, Frank K, Chin L, Alt FW, DePinho RA: Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions. Mol Cell 2001, 8(6):1187-1196.
• [32]Lee Y, McKinnon PJ: DNA ligase IV suppresses medulloblastoma formation. Cancer Res 2002, 62(22):6395-6399.
• [33]Yan CT, Kaushal D, Murphy M, Zhang Y, Datta A, Chen C, Monroe B, Mostoslavsky G, Coakley K, Gao Y, Mills KD, Fazeli AP, Tepsuporn S, Hall G, Mulligan R, Fox E, Bronson R, De Girolami U, Lee C, Alt FW: XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice. Proc Natl Acad Sci USA 2006, 103(19):7378-7383.
• [34]Jiang Z, Hu J, Li X, Jiang Y, Zhou W, Lu D: Expression analyses of 27 DNA repair genes in astrocytoma by TaqMan low-density array. Neurosci Lett 2006, 409(2):112-117.
• [35]Albino AP, Huang X, Jorgensen ED, Gietl D, Traganos F, Darzynkiewicz Z: Induction of DNA double-strand breaks in A549 and normal human pulmonary epithelial cells by cigarette smoke is mediated by free radicals. Int J Oncol 2006, 28(6):1491-1505.
• [36]Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B, Simon M, Marie Y, Boisselier B, Delattre JY, Hoang-Xuan K, El Hallani S, Idbaih A, Zelenika D, Andersson U, Henriksson R, Bergenheim AT, Feychting M, Lonn S, Ahlbom A, Schramm J, Linnebank M, Hemminki K, Kumar R, Hepworth SJ, Price A, Armstrong G, Liu Y, Gu X, Yu R: Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet 2009, 41(8):899-904.
• [37]Wrensch M, Jenkins RB, Chang JS, Yeh RF, Xiao Y, Decker PA, Ballman KV, Berger M, Buckner JC, Chang S, Giannini C, Halder C, Kollmeyer TM, Kosel ML, LaChance DH, McCoy L, O’Neill BP, Patoka J, Pico AR, Prados M, Quesenberry C, Rice T, Rynearson AL, Smirnov I, Tihan T, Wiemels J, Yang P, Wiencke JK: Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat Genet 2009, 41(8):905-908.