Search

Glioma is the most common malignant primary brain tumors with poor prognosis. Genome wide association studies (GWAS) of glioma in populations with Western European ancestry were completed in the US and UK. However, our previous results strongly suggest the genetic heterogeneity could be important in glioma risk. To systematically investigate glioma risk-associated variants in Chinese population, we performed a multistage GWAS of glioma in the Han Chinese population, with a total of 3,097 glioma cases and 4,362 controls. In addition to confirming two associations reported in other ancestry groups, this study identified one new risk-associated locus for glioma on chromosome 12p11.23 (rs10842893, p meta = 2.33x10-12, STK38L) as well as a promising association at 15q15-21.1 (rs4774756, p meta = 6.12x10-8, RAB27A) in 3,097 glioma cases and 4,362 controls. Our findings demonstrate two novel association between the glioma risk region marked by variant rs10842893 and rs4774756) and glioma risk. These findings may advance the understanding of genetic susceptibility to glioma., (© 2019 UICC.)

Glioma is one of the most common and lethal brain tumors. N-myc (and STAT) interactor (NMI) gene has been reported in tumorigenesis, and our previous study further showed its implication in glioma progression. To elucidate its involvement in the etiology of glioma, we conducted a case-control study of 875 patients and 1040 controls in a Chinese Han population by genotyping 7 representative single nucleotide polymorphisms (SNPs) in NMI. Allele and genotype frequency distribution of five loci (rs2278089, rs2194492, rs6734376, rs3854012, and rs11730) were significantly different between the cases and controls. Unconditional logistic regression showed that the variant genotypes of rs2278089 [adjusted odds ratio (OR) = 1.57, P = 4.23 × 10(-6)], rs2194492 (adjusted OR = 1.49, P = 1.20 × 10(-4)), and rs6734376 (adjusted OR = 0.06, P = 8.65 × 10(-13)) significantly affected glioma risk compared with the major homozygotes, while the minor homozygotes of rs3854012 (adjusted OR = 0.54, P = 4.64 × 10(-6)) and rs11730 (adjusted OR = 0.60, P = 1.50 × 10(-4)) showed significant protective effects. Further stratified analyses indicated that these associations remained significant in subgroups of low-grade glioma (LGG) and high-grade glioma (HGG). Additionally, haplotype and diplotype analyses showed consistent results. The Bonferroni correction was applied for all these analyses. Moreover, luciferase reporter gene assays revealed enhanced promoter activity of the C risk allele of rs2194492 in several cell lines compared with the G major allele, suggesting its potential function in transcriptional activation of NMI. Taken together, these results revealed that NMI polymorphisms may contribute to genetic susceptibility to glioma.

Background: Malignant glioma is a common and lethal primary brain tumor in adults. Here we identified a novel oncoprotein, vesicle-associated membrane protein 8 (VAMP8), and investigated its roles in tumorigenisis and chemoresistance in glioma., Methods: The expression of gene and protein were determined by quantitative PCR and Western blot, respectively. Histological analysis of 282 glioma samples and 12 normal controls was performed by Pearson's chi-squared test. Survival analysis was performed using the log-rank test and Cox proportional hazards regression. Cell proliferation and cytotoxicity assay were conducted using Cell Counting Kit-8. Autophagy was detected by confocal microscopy and Western blot., Results: VAMP8 was significantly overexpressed in human glioma specimens and could become a potential novel prognostic and treatment-predictive marker for glioma patients. Overexpression of VAMP8 promoted cell proliferation in vitro and in vivo, whereas knockdown of VAMP8 attenuated glioma growth by arresting cell cycle in the G0/G1 phase. Moreover, VAMP8 contributed to temozolomide (TMZ) resistance by elevating the expression levels of autophagy proteins and the number of autophagosomes. Further inhibition of autophagy via siRNA-mediated knockdown of autophagy-related gene 5 (ATG5) or syntaxin 17 (STX17) reversed TMZ resistance in VAMP8-overexpressing cells, while silencing of VAMP8 impaired the autophagic flux and alleviated TMZ resistance in glioma cells., Conclusion: Our findings identified VAMP8 as a novel oncogene by promoting cell proliferation and therapeutic resistance in glioma. Targeting VAMP8 may serve as a potential therapeutic regimen for the treatment of glioma., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Object: The retinoblastoma binding protein 6 (RBBP6) gene plays an important role in the induction of apoptosis and regulation of the cell cycle, and interacts with both p53 and retinoblastoma protein in carcinogenesis. Recently, many studies investigating the function of the RBBP6 gene, including its roles in lung cancer and breast cancer, have been reported. However, the association between RBBP6 variants and glioma was unknown. Therefore, to uncover the association between single nucleotide polymorphisms (SNPs) of RBBP6 and glioma, a hospital-based case-control study was performed in a Chinese Han population., Methods: Ten common tagging SNPs of the RBBP6 gene (covering 100% of all SNPs) were genotyped with the Sequenom MassARRY iPLEX platform, including 992 cases and 1008 controls, according to the HapMap database based on a pairwise linkage disequilibrium r(2) threshold of 0.8, minor allele frequency of 0.05, and Hardy-Weinberg equilibrium of 0.05., Results: The authors found that 4 SNPs were significantly associated with glioma (rs2033214, p = 0.013, adjusted OR 2.46, 95% CI 1.18-5.14; rs11860248, p = 8.64 × 10-(6), adjusted OR 1.59, 95% CI 1.23-2.05; rs9933544, p = 3.65 × 10(-4), adjusted OR 1.39, 95% CI 1.13-1.87; rs13332653, p = 0.004, adjusted OR 1.49, 95% CI 1.14-1.95). Stratification analyses revealed that rs2033214 was only significantly associated with low-grade gliomas; rs9933544 and rs13332653 were only significantly associated with glioblastoma multiforme; and rs11860248 was significantly associated with both low-grade gliomas and glioblastoma multiforme, compared with the common wild-type homozygous genotype. Further stratified analysis revealed that rs11860248 was more pronounced in certain subgroups: adults, males, histological types, and family history of cancer. What's more, the haplotype and diplotype analyses consistently revealed that the subjects carrying 1 copy of haplotype CCGCC had a 53% increased glioma risk compared with their corresponding noncarriers (p = 0.018, adjusted OR 1.53, 95% CI 1.08-2.17)., Conclusions: The authors' results suggested that RBBP6 gene variants are associated with glioma and contribute to glioma susceptibility, which was first reported elsewhere. Individuals with the so-called risk alleles might have an increased risk of glioma. These results might provide new insight into the occurrence of glioma.

Dysregulation of the amino acid transporter SLC7A7 is involved in multiple types of cancer including gliobastoma (GBM), the most malignant form of glioma. We hypothesized that SLC7A7 genetic variants may influence glioma risk. To test this hypothesis, we conducted a case-control study in 736 incident glioma cases and 793 cancer-free controls in a Chinese population by genotyping 22 common single nucleotide polymorphisms in SLC7A7. In single-locus analysis, we found an increased risk was associated with the variant genotypes of rs12888930 (adjusted odds ratio [OR] = 1.25, 95% confidence interval [CI] 1.02-1.54, P = 0.034), rs12433985 (adjusted OR = 1.38, 95%CI = 1.13-1.70), rs2065134 (adjusted OR = 1.43, 95% CI 1.05-1.95) in a dominant genetic model and rs12436190 (adjusted OR = 1.37, 95%CI 1.06-1.77) in a recessive model. Multivariate analysis confirmed that rs12433985 and rs2065134 were significant and independent risk factor for glioma as well as GBM subtype (for rs12433985, OR = 1.21, 95%CI 1.04-1.42, P = 0.016 for all types of gliomas and P = 0.013, OR = 1.30, 95%CI 1.06-1.60 for GBM. For rs2065134, OR = 1.39, 95%CI 1.02-1.89, P = 0.039 for all types of gliomas and OR = 1.66, 95%CI 1.12-2.24, P = 0.011). These results, for the first time, provide suggestive evidence of polymorphisms in SLC7A7 is involved in the aetiology of glioma.

Two genome-wide association studies (GWAS) have identified 5p15.33 (TERT-CLPTM1L) as one of the susceptible regions for glioma in European background. A replication research of our group highlighted the association signals in the TERT gene of this region in a Chinese Han population. To comprehensively explore the region of glioma association at 5p15.33 and to refine the potential causal variants to a smaller critical region, we conducted a fine-mapping association study among 983 cases and 1,024 controls in a Chinese Han population. Using Hapmap3 datasets as a reference, we genotyped 16 tag SNPs across this 87.9-kb region encompassing TERT. Significant association with glioma risk was observed for rs2853677 [GG vs. GA: adjusted OR = 1.46, p = 5.51 × 10(-6), GG vs. AA: adjusted OR = 1.72, p = 7.64 × 10(-6), GG vs. GA and AA: adjusted OR = 1.96, p = 6.8 × 10(-6)] in TERT and an uncommon CLPTM1L haplotype G-T-A of rs4635969, rs6554759 and rs414965 (haplotype frequency = 0.07) was associated with higher glioma risk compared with the most common G-C-G haplotype (adjusted OR = 1.44, simulated p = 6.00 × 10(-3) under additive model). Our results indicate that sequence variants in the region flanking rs2853677 may account for the GWAS and replication signals identified in 5p15.33 for glioma susceptibility in Chinese population; besides, haplotype G-T-A in CLPTM1L also confers a risk to glioma suggesting CLPTM1L is also involved in the etiology of glioma. Additional studies especially those taking advantage of sequencing platforms are warranted to further confirm the conclusions and go deeper with our findings., (Copyright © 2012 UICC.)

Matrix metallopeptidases (MMPs) play an important role in central nervous system tumor growth, invasion and spreading. The currently available data provide clear evidence for the involvement of MMP3 in the pathophysiology of glioma. The study aims to explore the association of single nucleotide polymorphisms (SNPs) across the MMP3 gene with glioma risk. Three haplotype tagging and additional two promoter SNPs were genotyped among 766 glioma patients and 824 cancer-free controls from East China. None of these polymorphisms alone had a significant effect on risk of gliomas. However, when three promoter polymorphisms were evaluated together by the number of putative risk of genotypes (i.e., rs645419AA, 632478CA+AA, rs522616AA), a statistically significantly increased risk of gliomas was associated with the combined genotypes with two to three risk genotypes, compared with those with zero to one risk genotypes (adjusted odds ratio (OR) = 1.32; 95% confidence interval (CI) = 1.03-1.68). This increased risk was also more pronounced among adults (adjusted OR = 1.14, 95%CI = 1.02-1.27), males (adjusted OR = 1.19, 95%CI = 1.05-1.36), smokers (adjusted OR = 1.28, 95%CI = 1.07-1.52), subjects with no family history of cancer (adjusted OR = 1.21, 95%CI = 1.07-1.37), and patients with nonastrocytic gliomas (adjusted OR = 1.23, 95%CI = 1.06-1.43). In summary, our results suggest that any one of MMP3 variants may not have a substantial effect on glioma risk, but a joint effect of MMP3 promoter polymorphisms may contribute to risk of gliomas, particularly for adult gliomas., (Copyright © 2011 Wiley Periodicals, Inc.)

Genome-wide association studies have identified the susceptibility single nucleotide polymorphisms (SNPs) of glioma at chromosome 20q13.33, and the replication study conducted among Chinese Han population also confirmed the susceptibility locus rs6010620 is located in this region. To identify other genetic variants in 20q13.33, we genotyped 13 common tagging SNPs and imputed 86 additional SNPs in a region ∼100 kb at 20q13.33 among 1027 controls and 987 cases. Among 99 SNPs, five independent susceptibility loci (20-62315594 in RTEL1, 20-62335293 in adenosine diphosphate ribosylation factor-related protein 1, rs3761121 in ZGPAT, rs1058319 in SLC2A4RG and rs5019252 in ZBTB46) were identified for glioma. Two of the five SNPs (20-62335293, P = 3.09 × 10(-10) and rs1058319, P = 1.26 × 10(-11)) satisfied the threshold of genome-wide significance (P < 10(-8)). Further stratified analysis revealed that 20-62315594 was only significantly associated with glioblastoma (GBM) risk [P = 1.71 × 10(-8) for trend test, adjusted odds ratio (OR) = 1.99, 95% confidence interval (CI) = 1.57-2.52]. Other four SNPs were significantly associated with both GBM and astrocytoma. The risk of glioma increased with the increase of the number of risk alleles (P = 1.94 × 10(-11), for trend test, adjusted OR = 1.43, 95% CI = 1.29-1.58), and the individuals who carried 7-10 risk alleles had a 2.64-fold increased risk of glioma development compared with those who carried 0 risk allele (P = 8.71 × 10(-7), adjusted OR = 2.64, 95% CI = 1.79-3.88). Our results indicated a complex effect contributing to glioma risk at 20q13.33, which may provide a new insight into glioma development. Both variants and genes in this region should be considered in future studies designed to investigate the biological functions.

Background: A single nucleotide polymorphism (SNP) at locus 11q23.3 (rs498872) in the near 5'-UTR of the PHLDB1 gene was recently implicated as a risk factor for gliomas in a genome-wide association study, and this involvement was confirmed in three additional studies., Methodology/principal Findings: To identify possible causal variants in the region, the authors genotyped 15 tagging SNPs in the 200 kb genomic region at 11q23.3 locus in a Chinese Han population-based case-control study with 983 cases and 1024 controls. We found evidence for an association between two independent loci (both the PHLDB1 and the ACRN1 genes) and a predisposition for gliomas. Among the multiple significant SNPs in the PHLDB1 gene region, the rs17749 SNP was the most significant [P = 1.31×10⁻⁶ in a recessive genetic model]. Additionally, two novel SNPs (rs2236661 and rs494560) that were independent of rs17749 were significantly associated with glioma risk in a recessive genetic model [P = 1.31×10⁻⁵ and P = 3.32×10⁻⁵, respectively]. The second novel locus was within the ARCN1 gene, and it was associated with a significantly reduced risk for glioma., Conclusions/significance: Our data strongly support PHLDB1 as a susceptibility gene for glioma, also shedding light on a new potentially candidate gene, ARCN1.

H2AFX, a histone H2A gene family member X, is a key component in the detection of and response to DNA double-strand breaks (DSBs) caused by ionizing radiation (IR), a known risk factor for glioma. Thus, genetic variants in the H2AFX promoter region that may result in abnormal protein expression could confer susceptibility to glioma. In this case-control study, we genotyped three common single-nucleotide polymorphisms (SNPs) (rs643788, rs8551, and rs2509851) in the H2AFX promoter region in 669 adult glioma patients and 638 cancer-free controls. The associations between each SNP or haplotype and glioma risk were estimated by calculating odds ratios (ORs) and the corresponding 95% confidence interval (CI) using unconditional logistic regression models, with adjustment for age and sex. The H2AFX rs643788 A variant genotypes were significantly associated with reduced risk of glioma (GA versus GG: adjusted OR = 0.72, 95% CI = 0.56-0.94; GA/AA versus GG: adjusted OR = 0.75, 95% CI = 0.59-0.94), compared with the common GG genotype. Furthermore, this decreased risk was more evident among those aged ≥ 45 years (adjusted OR = 0.64, 95% CI = 0.45-0.90), male subjects (adjusted OR = 0.70, 95% CI = 0.50-0.96), and patients with glioblastoma (adjusted OR = 0.66, 95% CI = 0.46-0.94). These results suggest that a common variant in the H2AFX promoter region may modulate risk of glioma, particularly for adult glioma. However, our findings need to be replicated in other independent populations.

Glioma is one of the most common and lethal brain tumors. N-myc (and STAT) interactor ( NMI) gene has been reported in tumorigenesis, and our previous study further showed its implication in glioma progression. To elucidate its involvement in the etiology of glioma, we conducted a case-control study of 875 patients and 1040 controls in a Chinese Han population by genotyping 7 representative single nucleotide polymorphisms (SNPs) in NMI. Allele and genotype frequency distribution of five loci (rs2278089, rs2194492, rs6734376, rs3854012, and rs11730) were significantly different between the cases and controls. Unconditional logistic regression showed that the variant genotypes of rs2278089 [adjusted odds ratio (OR) = 1.57, P = 4.23 × 10], rs2194492 (adjusted OR = 1.49, P = 1.20 × 10), and rs6734376 (adjusted OR = 0.06, P = 8.65 × 10) significantly affected glioma risk compared with the major homozygotes, while the minor homozygotes of rs3854012 (adjusted OR = 0.54, P = 4.64 × 10) and rs11730 (adjusted OR = 0.60, P = 1.50 × 10) showed significant protective effects. Further stratified analyses indicated that these associations remained significant in subgroups of low-grade glioma (LGG) and high-grade glioma (HGG). Additionally, haplotype and diplotype analyses showed consistent results. The Bonferroni correction was applied for all these analyses. Moreover, luciferase reporter gene assays revealed enhanced promoter activity of the C risk allele of rs2194492 in several cell lines compared with the G major allele, suggesting its potential function in transcriptional activation of NMI. Taken together, these results revealed that NMI polymorphisms may contribute to genetic susceptibility to glioma. [ABSTRACT FROM AUTHOR]