The associations between glioma susceptibility loci and pathological parameters define specific molecular etiologies

Abstract

BACKGROUND: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in seven loci at 5p15.33 (TERT), 7p11.2 (EGFR, two loci), 8q24.21 (CCDC26), 9p21.3 (CDKN2A/CDKN2B), 20q13.33 (RTEL1) and 11q23.3 (PHLDB1) influencing glioma risk. Since gliomas are heterogeneous tumors we investigated the relationship between SNP genotype and glioma subtype. MATERIALS AND METHODS: We studied the relationship between rs2736100 (5p15.33), rs11979158 and rs2252586 (7p11.2 ), rs4295627 (8q24.21), rs4977756 (9p21.3), rs6010620 (20q13.33) and rs498872 (11q23.3) genotype and IDH1 mutation, EGFR amplification, CDKN2A-p16-INK4a homozygous deletion, 9p and 10q loss, 1p-19q co-deletion in tumors from 1,374 patients. RESULTS: rs2736100 (5p15.33, TERT) and rs6010620 (20q13.33, RTEL1) risk alleles were associated with high grade, EGFR amplification, CDKN2A homozygous deletion, 9p deletion and 10q deletion; rs4295627 (8q24.21, CCDC26), rs498872 (11q23.3, PHLDB1) were associated with low grade gliomas, IDH1 mutation, 1p-19q codeletion. In contrast, rs11979158 and rs2252586 (7p11.2, EGFR) and rs4977756 (9p21.3, CDKN2A/B) risk alleles were independent of tumor grade and genetic profile. After multivariate analysis, rs2736100 (5p15.33, TERT), rs4295627 (8q24.21, CCDC26), and rs498872 (11q23.3, PHLDB1) risk loci remained associated with tumor alterations -loss of 10q, CDKN2A homozygous deletion and 1p19q codeletion- independently from grade. CONCLUSION: The frequency of EGFR and CDKN2A/B risk alleles were independent of tumor genetic profile, whereas TERT, RTEL1, CCDC26, PHLDB1 variants were associated with different genetic profiles which annotate distinct molecular pathways. Our findings provide novel insight into biological basis of glioma etiology.