DNA-repair gene variants are associated with glioblastoma survival.

Patient outcome from glioma may be influenced by germline variation. Considering the importance of DNA repair in cancer biology as well as in response to treatment, we studied the relationship between 1458 SNPs, which captured the majority of the common genetic variation in 136 DNA repair genes, in 138 glioblastoma samples from Sweden and Denmark. We confirmed our findings in an independent cohort of 121 glioblastoma patients from the UK. Our analysis revealed nine SNPs annotating MSH2, RAD51L1 and RECQL4 that were significantly (p < 0.05) associated with glioblastoma survival.

Human immunoglobulin G levels of viruses and associated glioma risk.

Few consistent etiological factors have been identified for primary brain tumors. Inverse associations to asthma and low levels of varicella-zoster virus, immunoglobulin (Ig) levels in prevalent cases have indicted a role for the immune system in the development of glioma. Because samples from prevalent cases of glioma could be influenced by treatments such as steroids and chemotherapy, we investigated pre-diagnostic samples from three large Scandinavian cohorts. To test the hypothesis that immune response levels to these viruses are associated etiologically with glioma risk, we investigated pre-diagnostic immunoglobulin levels for cytomegalovirus (CMV), varicella-zoster virus (VZV), adenovirus (Ad), and Epstein-Barr virus (EBV) including the nuclear antigen (EBNA1) using plasma samples from 197 cases of adult glioma and 394 controls collected from population-based cohorts in Sweden and Denmark. Low VZV IgG levels were marginally significantly more common in glioma cases than the controls (odds ratio (OR) = 0.68, 95% CI 0.41-1.13) for the fourth compared with the first quartile (p = 0.06 for trend). These results were more prominent when analyzing cases with blood sampling at least 2 years before diagnosis (OR = 0.63, 95% CI 0.37-1.08) (p = 0.03). No association with glioma risk was observed for CMV, EBV, and adenovirus.

Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas.

The purpose of this study was to explore the variation in DNA repair genes in adults with WHO grade II and III gliomas and their relationship to patient survival. We analysed a total of 1,458 tagging single-nucleotide polymorphisms (SNPs) that were selected to cover DNA repair genes, in 81 grade II and grade III gliomas samples, collected in Sweden and Denmark. The statistically significant genetic variants from the first dataset (P < 0.05) were taken forward for confirmation in a second dataset of 72 grade II and III gliomas from northern UK. In this dataset, eight gene variants mapping to five different DNA repair genes (ATM, NEIL1, NEIL2, ERCC6 and RPA4) which were associated with survival. Finally, these eight genetic variants were adjusted for treatment, malignancy grade, patient age and gender, leaving one variant, rs4253079, mapped to ERCC6, with a significant association to survival (OR 0.184, 95% CI 0.054-0.63, P = 0.007). We suggest a possible novel association between rs4253079 and survival in this group of patients with low-grade and anaplastic gliomas that needs confirmation in larger datasets.

A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk.

Glioma is the most common type of adult brain tumor and glioblastoma, its most aggressive form, has a dismal prognosis. Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR, ERBB2, ERBB3, ERBB4) family, and the vascular endothelial growth factor receptor (VEGFR), play a central role in tumor progression. We investigated the genetic variants of EGFR, ERBB2, VEGFR and their ligands, EGF and VEGF on glioma and glioblastoma risk. In addition, we evaluated the association of genetic variants of a newly discovered family of genes known to interact with EGFR: LRIG2 and LRIG3 with glioma and glioblastoma risk. Methods. We analyzed 191 tag single nucleotide polymorphisms (SNPs) capturing all common genetic variation of EGF, EGFR, ERBB2, LRIG2, LRIG3, VEGF and VEGFR2 genes. Material from four case-control studies with 725 glioma patients (329 of who were glioblastoma patients) and their 1 610 controls was used. Haplotype analyses were conducted using SAS/Genetics software. Results. Fourteen of the SNPs were significantly associated with glioma risk at p< 0.05, and 17 of the SNPs were significantly associated with glioblastoma risk at p< 0.05. In addition, we found that one EGFR haplotype was related to increased glioblastoma risk at p=0.009, Odds Ratio [OR] = 1.67 (95% confidence interval (CI): 1.14, 2.45). The Bonferroni correction made all p-values non-significant. One SNP, rs4947986 next to the intron/exon boundary of exon 7 in EGFR, was validated in an independent data set of 713 glioblastoma and 2 236 controls, [OR] = 1.42 (95% CI: 1.06,1.91). Discussion. Previous studies show that regulation of the EGFR pathway plays a role in glioma progression but the present study is the first to find that certain genotypes of the EGFR gene may be related to glioblastoma risk. Further studies are required to reinvestigate these findings and evaluate the functional significance.

Genetic variations in EGF and EGFR and glioblastoma outcome.

Few prognostic factors have been associated with glioblastoma survival. We analyzed a complete tagging of the epidermal growth factor (EGF) and EGF receptor (EGFR) gene polymorphisms as potential prognostic factors. Thirty tagging single-nucleotide polymorphisms (SNPs) in EGF and 89 tagging SNPs in EGFR were analyzed for association with survival in 176 glioblastoma cases. Validation analyses were performed for 4 SNPs in a set of 638 glioblastoma patients recruited at The University of Texas M. D. Anderson Cancer Center (MDACC). Three hundred and seventy-four glioblastoma patients aged 50 years or older at diagnosis were subanalyzed to enrich for de novo arising glioblastoma. We found 7 SNPs in haplotype 4 in EGF that were associated with prognosis in glioblastoma patients. In EGFR, 4 of 89 SNPs were significantly associated with prognosis but judged as false positives. Four of the significantly associated EGF polymorphisms in haplotype block 4 were validated in a set from MDACC; however, none of the associations were clearly replicated. rs379644 had a hazard ratio (HR) of 1.19 (0.94-1.51) in the whole population with 18.6 months survival in the risk genotype compared with 24.5 in the reference category. As the median age differed slightly between the 2 study sets, the MDACC cases aged 50 or older at diagnosis were analyzed separately (rs379644, HR 1.32 [0.99-1.78]), which is marginally significant and partially validates our findings. This study is, to our knowledge, the first to perform a comprehensive tagging of the EGF and EGFR genes, and the data give some support that EGF polymorphisms might be associated with poor prognosis. Further confirmation in independent data sets of prospective studies is necessary to establish EGF as prognostic risk factor.

MNS16A minisatellite genotypes in relation to risk of glioma and meningioma and to glioblastoma outcome.

The human telomerase reverse transcriptase (hTERT) gene is upregulated in a majority of malignant tumours. A variable tandem repeat, MNS16A, has been reported to be of functional significance for hTERT expression. Published data on the clinical relevance of MNS16A variants in brain tumours have been contradictory. The present population-based study in the Nordic countries and the United Kingdom evaluated brain-tumour risk and survival in relation to MNS16A minisatellite variants in 648 glioma cases, 473 meningioma cases and 1,359 age, sex and geographically matched controls. By PCR-based genotyping all study subjects with fragments of 240 or 271 bp were judged as having short (S) alleles and subjects with 299 or 331 bp fragments as having long (L) alleles. Relative risk of glioma or meningioma was estimated with logistic regression adjusting for age, sex and country. Overall survival was analysed using Kaplan-Meier estimates and equality of survival distributions using the log-rank test and Cox proportional hazard ratios. The MNS16A genotype was not associated with risk of occurrence of glioma, glioblastoma (GBM) or meningioma. For GBM there were median survivals of 15.3, 11.0 and 10.7 months for the LL, LS and SS genotypes, respectively; the hazard ratio for having the LS genotype compared with the LL was significantly increased HR 2.44 (1.56-3.82) and having the SS genotype versus the LL was nonsignificantly increased HR 1.46 (0.81-2.61). When comparing the LL versus having one of the potentially functional variants LS and SS, the HR was 2.10 (1.41-3.1). However, functionality was not supported as there was no trend towards increasing HR with number of S alleles. Collected data from our and previous studies regarding both risk and survival for the MNS16A genotypes are contradictory and warrant further investigations.