Age-specific genome-wide association study in glioblastoma identifies increased proportion of ‘lower grade glioma’-like features associated with younger age

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18–53, 54–64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p_54–63 = 1.50x10⁻⁹, OR_54–63 = 1.28, 95%CI_54–63 = 1.18–1.39; p₆₄₊ = 2.14x10⁻¹¹, OR₆₄₊ = 1.32, 95%CI₆₄₊ = 1.21–1.43] and rs11979158 [p_54–63 = 6.13x10⁻⁸, OR_54–63 = 1.35, 95%CI_54–63 = 1.21–1.50; p₆₄₊ = 2.18x10⁻¹⁰, OR₆₄₊ = 1.42, 95%CI₆₄₊ = 1.27–1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18–53 (p_18–53 = 9.30 × 10⁻¹¹, OR_18–53 = 1.76, 95%CI_18–53 = 1.49–2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of ‘LGG’-like tumor characteristics in GBM samples in those 18–53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54–63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18–53 suggests that more younger individuals may present initially with ‘secondary glioblastoma.’.