Abstract
4680
The causes of brain tumors are largely unknown except for rare inherited syndromes and high doses of ionizing radiation, which can only explain a small fraction of incidence. Amplification of epidermal growth factor receptor (EGFR) is found in approximately 50% of high-grade gliomas suggesting that overexpression and/or gene alteration in this gene is an important event in tumorgenesis of gliomas. A common polymorphism in the EGFR promoter is associated with altered promoter activity and gene expression both in vitro and in vivo. It could therefore be proposed that brain tumors might be caused by susceptibility in single nucleotide polymorphisms (SNPs). In association studies, haplotype tag SNPs are selected on the basis of linkagedisequilibrium (LD) and can substantially reduce the amount of genotypingneeded per gene.However, EGFR is a large gene with low LD which makes it necessary to select a sufficient number of tag SNPs to cover all haplotype blocks located in the gene sequence. In this association study we selected 112 haplotype tag SNPs covering all haplotype blocks throughout the EGFR gene and tested the hypothesis that polymorphisms and haplotypes in EGFR might be associated with glioma and glioblastoma risk. Haplotype risks, adjusted for age, gender and country were estimated using SAS/Genetics software. 607 glioma cases (269 glioblastomas), and 1286 controls recruited in the Nordic-UK Interphone study were analyzed. The most significant tag SNPs covering the gene were used to estimate haplotypes associated for risk. The haplotype analysis in EGFR showed a higher frequency of the c-g-c-g-t-g-a-g-a-c-g-g haplotype in gliomas (6%) compared with controls (5%). This haplotype was associated with borderline significantly increased risk (odds ratio (OR) = 2.2; CI, 95% 1.01, 4.81). When analyzing glioblastomas separately, the frequency was higher in glioblastomas (12%) compared with controls (5%) and more significantly associated with increased risk (OR = 4.18; CI, 1.73, 10.1). As far as we know this is the first study in which regions of the EGFR gene has been analyzed extensively for variants that may influence glioma risk. The findings reveal potential associations of a risk haplotype in EGFR for both gliomas and glioblastomas. Our future research intended in this area includes functional studies which are important to find out if haplotypes associated with increased risk of glioma truly affect the tumor phenotype.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA