Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk - PubMed (original) (raw)

Comparative Study

doi: 10.1038/ng.3004. Epub 2014 Jun 8.

Veryan Codd 2, Ivan V Smirnov 3, Terri Rice 4, Paul A Decker 5, Helen M Hansen 4, Thomas Kollmeyer 6, Matthew L Kosel 5, Annette M Molinaro 3, Lucie S McCoy 4, Paige M Bracci 7, Belinda S Cabriga 4, Melike Pekmezci 8, Shichun Zheng 4, Joseph L Wiemels 9, Alexander R Pico 10, Tarik Tihan 8, Mitchell S Berger 3, Susan M Chang 3, Michael D Prados 3, Daniel H Lachance 11, Brian Patrick O'Neill 11, Hugues Sicotte 5, Jeanette E Eckel-Passow 5; ENGAGE Consortium Telomere Group; Pim van der Harst 12, John K Wiencke 13, Nilesh J Samani 2, Robert B Jenkins 6, Margaret R Wrensch 13

Collaborators, Affiliations

Comparative Study

Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk

Kyle M Walsh et al. Nat Genet. 2014 Jul.

Abstract

Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10(-20) and 4.4 × 10(-19), respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.

PubMed Disclaimer

Figures

Figure 1

Figure 1. SNP association plots for high-grade glioma risk and mean leukocyte telomere length at 3q26.2 (TERC), 5p15.33 (TERT), and 20q13.33 (RTEL1)

Telomere associations (grey squares) are from the telomere length genome-wide association meta-analysis (N=37684). Glioma associations (red circles) are from the genome-wide discovery meta-analysis, combining data from the UCSF Adult Glioma Study, The Cancer Genome Atlas, and the Wellcome Trust Case-Control Consortium (N=1013 cases and 6595 controls). Red diamonds are from the combined glioma discovery and UCSF and Mayo Clinic replication analyses (1644 cases, 7736 controls).

Figure 2

Figure 2. SNP association plots indicating the –log10_P_ for association with high-grade glioma risk (y-axis) and mean leukocyte telomere length (x-axis)

Colors correspond to whether the glioma risk allele is associated with longer (blue) or shorter (orange) leukocyte telomere length.

References

    1. Codd V, et al. Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet. 2013;45:422–7. 427e1–2. -PMC -PubMed
    1. Stupp R, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66. -PubMed
    1. Sanson M, et al. Chromosome 7p11. EGFR) variation influences glioma risk. Hum Mol Genet. 2011;20:2897–904. -PMC -PubMed
    1. Shete S, et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet. 2009;41:899–904. -PMC -PubMed
    1. Stacey SN, et al. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nat Genet. 2011;43:1098–103. -PMC -PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources