ED-36INHERITED VARIANTS NEAR TERC AND TERT ARE ASSOCIATED WITH LONGER TELOMERES AND INCREASED GLIOMA RISK: GENOME-WIDE ASSOCIATION RESULTS FROM THE UCSF ADULT GLIOMA STUDY AND THE ENGAGE CONSORTIUM TELOMERE GROUP

ABSTRACT: High-grade glioma, the most common central nervous system cancer in adults, has poor prognosis. We performed a genome-wide association study (GWAS) and replication analysis of high-grade glioma risk (N = 1,644 cases and 7,736 controls). We identify a novel inherited glioma risk locus, rs1920116 (near TERC), that achieved genome-wide statistical significance (Pcombined = 8.3 × 10?9). We also validate a previously identified glioma risk locus, rs2736100, in TERT (Pcombined = 1.4 × 10?15). Because TERC and TERT are subunits of the telomerase enzyme, and variants in both genes have previously been associated with mean leukocyte telomere length (LTL), we examined the relationship between telomere length and glioma risk loci using data from a recent GWAS of LTL (N = 37,684 individuals). The top glioma risk alleles near TERC and TERT were strongly associated with longer telomere length (P = 5.5 × 10?20 and 4.4 × 10?19, respectively). In a ?100kb haplotype block containing the TERC gene, every SNP which was associated with glioma at P < 0.01 (N = 54 SNPs) was also associated with longer telomeres at P < 1.0x10?5. Associations in TERT were similarly uniform. Glioma risk alleles near RTEL1 were inconsistently associated with telomere length, suggesting the presence of distinct causal alleles at this locus. No other glioma risk loci were associated with telomere length. The identification of alleles that are strongly associated with both increased glioma risk and longer telomeres suggests that heritable variation in telomere length or telomerase activity may underlie glioma susceptibility.

SUBMITTER: Walsh K 

PROVIDER: S-EPMC4218077 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature