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), OR54-63 = 1.28, 95%CI54-63 = 1.18-1.39; p(64+) = 2.14x10(-11), OR64+ = 1.32, 95%CI64+ = 1.21-1.43] and rs11979158 [p(54-63) = 6.13x10(-8), OR54-63 = 1.35, 95%CI54-63 = 1.21-1.50; p(64+) = 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 x 10(-11), OR18-53 = 1.76, 95%CI18-53 = 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.' What's new? The authors performed the first genome-wide association analysis examining age-at-diagnosis and germline risk variants in glioblastoma. They report a higher frequency of germline variants associated with lower grade gliomas (LGG) in the younger cohort (age 18-53), as well as high frequency of LGG-like somatic variants in The Cancer Genome Atlas Glioblastoma cohort. This could indicate that glioblastoma at a younger age might more often evolve from an LGG (secondary glioblastoma) than at an older age and should be taken into consideration when molecular classification is not available.

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