Two genome-wide association studies of glioma in European populations identified 14 genetic variants strongly associated with risk of glioma, but it is unknown whether these variants are associated with glioma risk in Asian populations. The authors genotyped these 14 variants in 976 glioma patients and 1,057 control subjects to evaluate their associations with risk of glioma, particularly high-grade glioma (glioblastoma; n = 312), in a Chinese population (2004-2009). Overall, the authors identified 3 susceptibility loci for glioma risk at 20q13.33 (RTEL1 rs6010620 (P = 2.79 × 10(-6))), 11q23.3 (PHLDB1 rs498872 (P = 3.8 × 10(-6))), and 5p15.33 (TERT rs2736100 (P = 3.69 × 10(-4))) in this study population; these loci were also associated with glioblastoma risk (20q13.33: RTEL1 rs6010620 (P = 3.57 × 10(-7)); 11q23.3: PHLDB1 rs498872 (P = 7.24 × 10(-3)); 5p15.33: TERT rs2736100 and TERT rs2736098 (P = 1.21 × 10(-4) and P = 2.84 × 10(-4), respectively)). This study provides further evidence for 3 glioma susceptibility regions at 20q13.33, 11q23.3, and 5p15.33 in Chinese populations.

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.

Several types of epidermal growth factor receptor (EGFR) gene alternations have been observed in human tumors. Here we present a novel EGFR variant with aberrant splicing of exon 4 (named as de4 EGFR). Variant-specific polymerase chain reaction showed that de4 EGFR was expressed in some glioma (4/40), prostate cancer (3/11), and ovarian cancer (3/9) tissues but not in tissues adjacent to tumors or normal tissues. de4 EGFR displayed an enhanced transformation and a higher metastasis-promoting capacity in comparison to wild-type EGFR. With minimal EGF-binding activity, de4 EGFR underwent ligand-independent autophosphorylation and self-dimerization. Moreover, in serum-starved condition, de4 EGFR expression in U87 MG cells significantly upregulated the extracellular signal-regulated kinase and AKT phosphorylation and expression of JUN and Src. Importantly, E-cadherin expression was barely detectable in the U87 MG cells expressing de4 EGFR and restored expression of E-cadherin in these cells inhibited their metastatic behaviors. Taken together, we identified a novel EGFR variant with increased metastasis-promoting activity that may become a promising new target for cancer therapy.