Genetic risk profiles identify different molecular etiologies for glioma

Purpose

Genome-wide association studies have recently identified single nucleotide polymorphisms in five loci at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A/CDKN2B), 20q13.33 (rs6010620, RTEL1) and 11q23.3 (rs498872, PHLDB1) to be associated with glioma risk. Since gliomas are heterogeneous in histology, molecular alterations and clinical behavior we have investigated these polymorphisms for potential correlations with tumor histology and patient survival.

Experimental Design

We studied the relationship between SNPs and glioma subtype in two large patient cohorts from France and Germany, totaling 1,577 patients as well as the relationship between SNP-genotype and overall survival.

Results

In both cohorts the frequencies of rs2736100 and rs6010620 risk genotypes were highly correlated with high-grade disease (P < 0.001) while rs4295627 and rs498872 risk genotypes were inversely related to tumor grade (P < 0.001). These data show that genetic variation at these loci have sub-type specific effects on the risk of developing glioma. In contrast rs4977756 genotype was not correlated with tumor grade consistent with the causal variant having a generic influence on glioma development. None of the five SNPs were associated with prognosis, independent of tumor grade.

Conclusions

Our findings provide novel insight into etiological pathways in the different glioma subtypes.