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

Walsh KM1, Codd V2, Smirnov IV3, Rice T4, Decker PA5, Hansen HM4, Kollmeyer T6, Kosel ML5, Molinaro AM3, McCoy LS4, Bracci PM7, Cabriga BS4, Pekmezci M8, Zheng S4, Wiemels JL9, Pico AR10, Tihan T8, Berger MS3, Chang SM3, Prados MD3, Lachance DH11, O'Neill BP11, Sicotte H5, Eckel-Passow JE5;ENGAGE Consortium Telomere Group, van der Harst P12, Wiencke JK13, Samani NJ2, Jenkins RB6, Wrensch MR13.

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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.