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Comparative Study
. 2013 Aug;15(8):1041-7.
doi: 10.1093/neuonc/not051. Epub 2013 Jun 3.

Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: evidence for distinct pathways of gliomagenesis

Kyle M Walsh  1 , Terri Rice, Paul A Decker, Matthew L Kosel, Thomas Kollmeyer, Helen M Hansen, Shichun Zheng, Lucie S McCoy, Paige M Bracci, Erik Anderson, George Hsuang, Joe L Wiemels, Alexander R Pico, Ivan Smirnov, Annette M Molinaro, Tarik Tihan, Mitchell S Berger, Susan M Chang, Michael D Prados, Daniel H Lachance, Hugues Sicotte, Jeanette E Eckel-Passow, John K Wiencke, Robert B Jenkins, Margaret R Wrensch
Affiliations
Comparative Study

Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: evidence for distinct pathways of gliomagenesis

Kyle M Walsh et al. Neuro Oncol. 2013 Aug.

Abstract

Background: Genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma.

Methods: SNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between "number of risk alleles" and "age at diagnosis," adjusted for sex and study site and stratified by tumor grade/histology where appropriate.

Results: Four SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10(-22) and P = 9.5 × 10(-7), respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10(-4) and P = 2.5 × 10(-4), respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups.

Conclusions: Carrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).

Keywords: age at diagnosis; glioma; single nucleotide polymorphism; telomerase; telomere.

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Figures

Fig. 1.
Fig. 1.
Changes in the magnitude of glioma risk associated with 4 SNPs across subject age strata in case-control analyses. Odds ratios for glioma were calculated in case-control analyses adjusted for sex and study site; 95% CIs appear around each effect estimate. The y axis is represented on a log-scale (base 2), ranging from 0.50 to 8.0 for Fig. 1A and 0.50 to 2.0 for Fig. 1B–1D.
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