Glioma Susceptibility 7

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Retrieved
2019-09-22
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For a general phenotypic description and a discussion of genetic heterogeneity of glioma, see GLM1 (137800).

Mapping

Working from the hypothesis that coinheritance of low-risk variants contributes to the 2-fold increased risk of glioma in relatives of individuals with primary brain tumors, Shete et al. (2009) conducted a metaanalysis of 2 glioma genomewide association studies by genotyping 550,000 tagged SNPs in a total of 1,878 cases and 3,670 controls, with validation in 3 additional independent series totaling 2,545 cases and 2,953 controls. The strongest association was achieved with the single-nucleotide polymorphism (SNP) rs4295627 (OR = 1.36, 95% CI 1.29-1.43, P = 2.34 x 10(-18)), which localizes to chromosome 8q24.21 in intron 3 of the CCDC26 gene (613040), a retinoic acid modulator of differentiation and death.

In a 2-stage study using tag SNP genotyping and imputation, pooled next-generation sequencing using long-range PCR, and subsequent validation SNP genotyping and involving 1,657 cases and 1,301 controls, Jenkins et al. (2012) identified 7 low frequency SNPs at 8q24.21 that were strongly associated with glioma risk (p = 1 x 10(-25) to 1 x 10(-14)). The most strongly associated SNP, rs55705857G, remained highly significant after individual adjustment for the other top 6 SNPs and the 2 SNPs identified by Shete et al. (2009), rs4295627 and rs891835. After stratifying by histologic and tumor genetic subtype, the most significant associations of rs55705857 were with oligodendroglial tumors (OR = 6.3, p = 2.2 x 10(-28)) and gliomas with mutant IDH1 (147700) (OR = 5.1, p = 1.1 x 10(-31)) or IDH2 (147650) (OR = 4.8, p = 6.6 x 10(-22)). Strong associations were observed for astrocytomas with mutated IDH1 or IDH2 (grades 2-4) (OR = 5.16-6.66, p = 4.7 x 10(-12) to 2.2 x 10(-8)) but not for astrocytomas with wildtype IDH1 and IDH2. The conserved sequence block that includes rs55705857 is consistently modeled as a microRNA.