rs498872

Age-stratified genome-wide association study of 4,512 glioblastoma cases and 10,582 controls identified age-specific genetic effects on disease susceptibility. SNPs at 7p11.2 (rs723527, rs11979158 near EGFR) showed increased association in older individuals (age 54+, OR=1.28-1.42), while a lower-grade glioma-associated SNP at 8q24.21 (rs55705857) was associated with younger diagnosis (age 18-53, OR=1.76, p=9.30×10−11). IDH1/2 mutations occurred in 15% of younger GBM cases versus 0.8-2.1% in older cases, suggesting many younger cases represent 'secondary GBM' with LGG-like features.

This study investigated the association of MGMT enhancer variant rs11016629 with glioma susceptibility and progression in 402 patients and 654 controls. The TG genotype was associated with increased glioma risk (OR=1.41, 95% CI 1.03-1.93, P=0.034), particularly in WHO grade IV tumors (OR=1.59, P=0.023). In patients who underwent gross total resection, carriers with TG/TT genotypes had worse progression-free survival (HR=2.66, 95% CI 1.23-5.79, P=0.014) compared to GG carriers.

A case-control study examining seven known glioma risk loci in individuals with a family history of brain tumours (104 FHBT-glioma cases, 2,868 controls). Three SNPs were associated with glioma risk: rs2736100 (TERT; OR=1.41, 95% CI 1.05-1.89), rs4977756 (CDKN2A-CDKN2B; OR=2.01, p=0.01), and rs6010620 (RTEL1; OR=0.51, p=0.012 for glioblastoma). Only rs6010620 remained significant after correction for multiple comparisons.

Genome-wide association study of glioma in 1,856 cases and 4,955 controls that confirmed seven previously reported susceptibility loci. Strong replication was found for rs2736100 (TERT, OR=0.72), rs4977756 (CDKN2BAS, OR=1.35), and rs6010620 (RTEL1, OR=0.66). Consistent associations were observed for loci at EGFR, CCDC26, and PHLDB1. Meta-analysis of 85 candidate loci in 5,015 cases and 11,601 controls identified no novel genome-wide significant associations, suggesting glioma genetic architecture may involve fewer common variants than other cancers.

This review discusses recent genome-wide association studies (GWAS) that identified five susceptibility loci for glioma: TERT rs2736100 (OR=1.27), CCDC26 rs4295627 (OR=1.36), CDKN2A/CDKN2B rs4977756 (OR=1.24), RTEL1 rs6010620 (OR=1.18), and PHLDB1 rs498872 (OR=1.28). The combined effect shows that individuals with 8 or more risk alleles have over 3-fold increased glioma risk compared to those with median alleles (OR=1.31 per allele, p=1.39×10^-74). These common low-risk variants represent the strongest evidence to date for inherited susceptibility to glioma, with shared associations across multiple cancer types.