TELOMERE LENGTH VARIANTS ARE ASSOCIATED WITH HIGH-GRADE GLIOMA RISK: IDENTIFICATION OF A NOVEL GLIOMA RISK LOCUS BY GENOME-WIDE ASSOCIATION STUDY

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Abstract

BACKGROUND: Glioblastoma, the most common and aggressive form of glioma, has a median survival time of just 15 months. Both inherited and acquired genetic variation influence gliomagenesis. Previous genome-wide association studies (GWAS) have discovered seven glioma risk loci, including two in genes involved in telomere structure and function (TERT and RTEL1). METHODS: To identify novel high-grade glioma risk loci, we performed SNP imputation and meta-analysis of genome-wide array data from The University of California, San Francisco Adult Glioma Study (AGS), The Cancer Genome Atlas (TCGA) and the Wellcome Trust Case-Control Consortium (WTCCC) (1,013 cases and 6,595 controls). SNPs with P < 1.0x10-6 in the discovery meta-analysis underwent attempted replication in an additional 631 glioblastoma cases and 1141 controls from The Mayo Clinic and UCSF. To investigate potential functional mechanisms through which SNPs might promote gliomagenesis, we examined the relationship between mean leukocyte telomere length (LTL) and glioma risk loci using data from a recent GWAS of LTL (N = 37,684). RESULTS: One novel SNP association from the discovery phase meta-analysis met criteria for attempted replication. This SNP was significantly associated with high-grade glioma risk in the replication dataset (P = 3.4x10-3). The combined P-value for all 1644 cases and 7736 controls achieved genome-wide statistical significance (8.3x10-9). Glioma risk alleles in both our newly identified risk region and the known TERT risk locus were strongly associated with longer LTL (P < 5.0x10-8). In contrast, glioma risk alleles near RTEL1 were inconsistently associated with LTL and suggested the presence of distinct causal alleles underlying these two phenotypes. No other established glioma risk loci were associated with LTL. CONCLUSIONS: We identify a novel genome-wide significant association between a constitutive SNP and glioma risk. Because telomere maintenance is a universal requirement of oncogenic progression and telomere length displays substantial interindividual variability, telomere length is a promising epidemiologic risk factor for human cancers. We demonstrate that alleles in our novel locus and in TERT are associated with both longer mean LTL and with increased glioma risk. These results strongly implicate inherited variation near these two genes in facilitating gliomagenesis through a mechanism involving lengthened telomeres. SECONDARY CATEGORY: n/a.

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