Tagging SNPs in non-homologous end-joining pathway genes and risk of glioma

Abstract

Ionizing radiation is known to cause DNA damage, including single-strand and double-strand DNA breaks (DSBs), and the unrepair of DNA damage, particularly DSBs, may cause chromosome aberrations. Although the etiology of gliomas remains unclear, exposure to ionizing radiation has been identified as the only established risk factor. We hypothesized that polymorphisms of candidate genes involved in the DSBs repair pathway may contribute to susceptibility to glioma. We used a haplotype-based approach to investigate the role of 22 tagging single-nucleotide polymorphisms (tSNPs) of XRCC5, XRCC6 and XRCC7 in 771 glioma patients and 752 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by the unconditional logistic regression, haplotypes were inferred by the HAPLO.STAT program and gene-gene interactions were evaluated by the multifactor dimensionality reduction method. We found that, in the single-locus analysis, glioma risk was statistically significantly associated with three XRCC5 tSNPs (SNP1 rs828704, SNP6 rs3770502 and SNP7 rs9288516, P = 0.005, 0.042 and 0.003, respectively), one XRCC6 tSNP (SNP4 rs6519265, P = 0.044) but none of XPCC7 tSNPs. Haplotype-based association analysis revealed that gliomas risk was statistically significantly associated with one protective XRCC5 haplotype "CAGTT," accounting for a 40% reduction (OR = 0.60, 95% CI = 0.43-0.85) in glioma risk, and some positive gene-gene interactions were also evident. In conclusion, genetic variants of the genes involved in the DSB repair pathway may play a role in the etiology of glioma.

Molecular Epidemiology of Primary Brain Tumors

“…We have listed about 20 epidemiological studies reporting positive associations between DNA repair polymorphisms and cancer risk (Table 1 [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] ). Only a small proportion of studies were large (five studies were more than 500 pair cases and controls) and population based; however, some consistencies in results are apparent.…”

XRCC3 haplotypes and risk of gliomas in a Chinese population: A hospital‐based case‐control study

“…In our previously published studies, we have demonstrated that some representative tSNPs of genes involved in the NHEJ pathway may modulate risk of gliomas. 23,24 Also, these results suggest that the genetic interaction between DNA repair genes may play an important role in the etiology of gliomas.…”

“…23,24 Briefly, all subjects, including case and control groups, were unrelated Han Chinese people from Shanghai City and its surrounding regions in east China. Patients newly diagnosed with pathologically confirmed gliomas were recruited into study group between October 2004 and May 2006 at the Department of Neurosurgery of Huashan Hospital of Fudan University, Shanghai, China.…”

Genomic Abnormalities in Gliomas

“…However, the results indicated possible associations between combinations of XRCC1 and XRCC3 SNPs and the risk of glioma development, as carriers of both homozygous variant genotypes, i.e., XRCC1 Gln399Gln and XRCC3 Met241Met were associated with a three-fold increased risk of glioma (OR = 3.18;95% CI,). In a haplotype-based approach in a Chinese population, Liu et al (2007) investigated the role of 22 tagging SNPs (tSNPs) of XRCC5, XRCC6 and XRCC7. They found that glioma risk was significantly associated with three of the XRCC5 tSNPs (rs828704, rs3770502 and rs9288516, P = 0.005, 0.042 and 0.003, respectively), one XRCC6 tSNP (rs6519265, P = 0.044), and none of the XPCC7 tSNPs in a single-locus analysis.…”