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

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Date
2018-11
ICR Author
Kinnersley, Benjamin
Houlston, Richard
Author
Ostrom, QT
Kinnersley, B
Armstrong, G
Rice, T
Chen, Y
Wiencke, JK
McCoy, LS
Hansen, HM
Amos, CI
Bernstein, JL
Claus, EB
Eckel-Passow, JE
Il'yasova, D
Johansen, C
Lachance, DH
Lai, RK
Merrell, RT
Olson, SH
Sadetzki, S
Schildkraut, JM
Shete, S
Rubin, JB
Andersson, U
Rajaraman, P
Chanock, SJ
Linet, MS
Wang, Z
Yeager, M
GliomaScan consortium
Houlston, RS
Jenkins, RB
Wrensch, MR
Melin, B
Bondy, ML
Barnholtz-Sloan, JS
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Type
Journal Article
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Abstract
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; p 64+ = 2.14x10 -11 , OR 64+ = 1.32, 95%CI 64+ = 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; p 64+ = 2.18x10 -10 , OR 64+ = 1.42, 95%CI 64+ = 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.'
URI
https://repository.icr.ac.uk/handle/internal/2681
DOI
https://doi.org/10.1002/ijc.31759
Collections
  • Genetics and Epidemiology
Subject
GliomaScan consortium
Humans
Glioblastoma
Brain Neoplasms
Case-Control Studies
Age Factors
Polymorphism, Single Nucleotide
Adolescent
Adult
Aged
Middle Aged
Female
Male
Genome-Wide Association Study
Young Adult
Neoplasm Grading
Research team
Cancer Genomics
Language
eng
Date accepted
2018-03-16
License start date
2018-11
Citation
International journal of cancer, 2018, 143 (10), pp. 2359 - 2366

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