The Genetic Architecture of Gliomagenesis-Genetic Risk Variants Linked to Specific Molecular Subtypes

Abstract

Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH-mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in TERT and TP53 were associated with increased risk of all glioma subtypes. Second, variants in CDKN2B-AS1, EGFR, and RTEL1 were associated with IDH-wildtype glioma. Third, variants in CCDC26 (the 8q24 locus), C2orf80 (close to IDH), LRIG1, PHLDB1, ETFA, MAML2 and ZBTB16 were associated with IDH-mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis.

Keywords: 1p/19q co-deletion; IDH mutant; etiopathogenesis; genotype phenotype; glioma; gliomagenesis.

Figure 1

The associations between 25 germline variants and molecular subgroups in the meta-analysis. The genetic variants were categorized into three groups: (red) associated with all glioma (All), (green) associated with IDH-wildtype (IDH-wt), and (blue) associated with IDH-mutant (IDH-mut). * p-value < 0.05, ** Bonferroni p-value < 0.05/75. Abbreviations: SNV: single nucleotide variant; NA: Not significant for molecular subtypes in the present study; OR: odds ratio; CI: confidence interval.

Figure 2

Three hypothesized pathways in gliomagenesis based on germline variants. (A) the overall glioma pathway, (B) the IDH wildtype pathway and (C) the IDH mutant pathway. The bold text represents statistically significant findings after adjusting for multiple comparisons. The asterisk (*) represents that the genes also have common somatic mutations in glioma.