Association between glioma susceptibility loci and tumour pathology defines specific molecular etiologies

Abstract

Background: Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) at 7 loci influencing glioma risk: rs2736100 (TERT), rs11979158 and rs2252586 (EGFR), rs4295627 (CCDC26), rs4977756 (CDKN2A/CDKN2B), rs498872 (PHLDB1), and rs6010620 (RTEL1).

Materials and methods: We studied the relationship among these 7 glioma-risk SNPs and characteristics of tumors from 1374 patients, including grade, IDH (ie IDH1 or IDH2) mutation, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, 9p and 10q loss, and 1p-19q codeletion.

Results: rs2736100 (TERT) and rs6010620 (RTEL1) risk alleles were associated with high-grade disease, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, and 9p and 10q deletion; rs4295627 (CCDC26) and rs498872 (PHLDB1) were associated with low-grade disease, IDH mutation, and 1p-19q codeletion. In contrast, rs4977756 (CDKN2A/B), rs11979158 (EGFR), and to a lesser extent, rs2252586 (EGFR) risk alleles were independent of tumor grade and genetic profile. Adjusting for tumor grade showed a significant association between rs2736100 and IDH status (P = .01), 10q loss (P = .02); rs4295627 and 1p-19q codeletion (P = .04), rs498872 and IDH (P = .02), 9p loss (P = .04), and 10q loss (P = .02). Case-control analyses stratified into 4 molecular classes (defined by 1p-19q status, IDH mutation, and EGFR amplification) showed an association of rs4295627 and rs498872 with IDH-mutated gliomas (P < 10(-3)) and rs2736100 and rs6010620 with IDH wild-type gliomas (P < 10(-3) and P = .03).

Conclusion: The frequency of EGFR and CDKN2A/B risk alleles were largely independent of tumor genetic profile, whereas TERT, RTEL1, CCDC26, and PHLDB1 variants were associated with different genetic profiles that annotate distinct molecular pathways. Our findings provide further insight into the biological basis of glioma etiology.

Fig. 1.

Kaplan–Meier curves in all glioma population show significant overall survival difference between tumor class 1-IDH mut/1p-19q codel/EGFR normal-(median OS 211.2 months), tumor class-2 IDH mut/1p-19q normal/EGFR normal-(median OS 103.9 months), tumor class 3-IDH wt/1p-19q normal/EGFR normal-(median OS 26.5 months), and tumor class 4-IDH wt/1p-19q normal/EGFR amplification-(median OS 16.6 months).

Fig. 2.

Glioma risk, stratified by specific tumor class, is represented (OR and 95% CI) for each single SNP. The data correspond to the Supplementary material, Table S6. ◊ IDH mutation/1p-19q codeletion/EGFR normal status; ▴ IDH mutation/1p-19q normal status/EGFR normal status; ○ IDH wild-type/1p-19q normal status/EGFR normal status; ▪ IDH wild-type/1p-19q normal status/EGFR amplification.