Two Common Gene Variants Associated With Longer Telomere Length May Increase the Risk of Glioma
Two common gene variants that lead to longer telomere length may increase the risk of glioma, according to the results of a study presented by Walsh et al in Nature Genetics. This finding suggests that telomere length may prove to be a promising epidemiologic risk factor for cancer.
It is well known that glioma in adults is associated with a poor prognosis. Indeed, patients with glioblastoma, the most common and aggressive form of glioma, have a median survival of 15 months.
To identify risk factors that may lead to glioblastoma, researchers have concentrated on both inherited and acquired factors such as the genes TERT and TERC. Mutations in these genes, including telomere length, have been observed in approximately 75% of glioblastomas. In the current study, Walsh and colleagues attempted to identify a new susceptibility locus for high-grade glioma near TERC and confirm that alleles for glioma risk near TERC and TERT influence telomere length.
Study Details and Results
The investigators conducted a meta-analysis of data (1,013 patients with glioma and 6,595 controls) from the University of California, San Francisco, The Cancer Genome Atlas, and the Wellcome Trust Case Control Consortium.
In the discovery phase, only rs1920116 on chromosome 3q26.2 was associated with glioma risk at P < 1.0 × 10−6 (P = 8.7×10−7); this association was also found to be significant in the replication data set (P = 3.4 × 10−3). Of note, alleles associated with glioma risk near TERC and TERT had similar effect sizes and were the major alleles in all regions.
In order to determine if loci associated with glioma risk influenced telomere length, the investigators examined single nucleotide polymorphism data from a recent genome-wide association study of mean leukocyte telomere length conducted in 37,684 individuals of European descent. The top alleles for glioma risk near TERC and TERT were strongly associated with longer leukocyte telomere length (P = 5.5 × 10−20 and 4.4 × 10−19, respectively); however, other loci known to be associated with a risk for glioma were not associated with leukocyte telomere length.
The investigators also compared the direction and statistical significance of associations in the TERC and TERT regions with high-grade glioma risk and mean leukocyte telomere length. They found that alleles in the TERC and TERT regions were consistently associated with both a higher risk of glioma and a longer leukocyte telomere length.
Additional analyses indicated that glioma risk might be influenced by multiple 3q26.2 single nucleotide polymorphisms, since controlling for either the lead single nucleotide polymorphism for glioma (rs1920116) or the lead single nucleotide polymorphism for leukocyte telomere length (rs10936599) did not fully reduce the association between glioma risk and nearby alleles. The investigators did suggest that rs1920116 might have long-range effects on gene expression.
The lack of association with leukocyte telomere length at other loci suggests that multiple mechanisms, including changes in telomere dynamics, may contribute to glioma risk. The results from this study also indicate that heritable variation might influence telomere dynamics in both normal and premalignant cells.
Clinical Implications
Telomere length has been shown to be an epidemiologic risk factor for cancer. It is known that mean telomere length decreases with age and may represent a biomarker of health. In addition, the investigators found that the alleles for glioma risk near TERC and TERT may also influence telomere length.
The investigators remarked, “Because telomere maintenance is a universal requirement for oncogenic progression and telomere length shows substantial interindividual variability, telomere length is a promising epidemiological risk factor for cancer.”
Kyle M Walsh, PhD, of the Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, California, is the corresponding author of the article in Nature Genetics.
This project was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, US National Institutes of Health, through a University of California, San Francisco, Clinical and Translational Science Institute grant. The authors reported no potential conflicts of interest.
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