A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation

Abstract

SNPs mapped to 8q24.21 have been shown to be associated with glioma development. By means of tag SNP genotyping/imputation, pooled next-generation sequencing (NGS) using long-range PCR, and subsequent validation SNP genotyping we identified seven low-frequency SNPs that were consistently and highly associated with glioma risk (p=10−25 to 10−14). The most associated SNP, rs55705857, remained highly significant after individual adjustment for the other top six and two previously published SNPs. After stratifying by histologic and tumor genetic subtype, the most significant associations were with oligodendroglial tumors and IDH1 or IDH2 mutated gliomas, (ORrs55705857 = 5.1, p=1.1x10−31 and ORrs55705857 = 4.8, p=6.6 x10−22, respectively). Strong associations were observed for IDH1 or IDH2 mutated astrocytomas (grades II–IV) (OR rs55705857=5.16–6.66; p=4.7x10−12 to 2.2x10−8), but not IDH1 or IDH2 wild-type astrocytomas (smallest p=0.26). The conserved sequence block that includes rs55705857 is consistently modeled as a microRNA.

Rare and uncommon genetic variants may hold key to the ‘missing heritability’ in glioma

“…In this regard, it is notable that the odds ratios (ORs) associated with rs55705857 G allele for all gliomas combined was markedly more elevated (per allele OR: ~3.1) than those reported for the SNPs tagging this locus (per allele ORs: 1.23-1.36) [3]. Strikingly, the excess risk associated with variant carrier status for this SNP in the report of Jenkins et al is on the order of five to six for oligodendroglial lineage gliomas and IDH1/2-mutant astrocytic gliomas, the most prominent risk association reported yet for a SNP identified through GWAS and subsequently validated through sequencing [7]. The minor allele frequency among people with these tumor types was 21%, compared with 5% in controls and approximately 3% in the general Caucasian population.…”

“…show conclusively that the rs55705857 germline variant intronic to CCDC26 predicts acquisition of IDH1/2 mutations in gliomas, one of the few such genotype/phenotype relationships yet established [7]. It is not yet clear whether the rs55705857 G allele actually facilitates the development of IDH1/2 mutation or confers a selective advantage to cells that acquire such mutations.…”

“…Of interest, Jenkins et al found that the presumptively causal SNP at 8q24 was associated with oligodendroglial lineage tumors (pure oligo dendrogliomas and mixed oligoastrocytomas), as well as astrocytic tumors of all grades that have acquired mutations in IDH1/2 [7]. In contrast, the variant was minimally associated with astrocytic lineage tumors not bearing IDH mutations.…”

“…The extent to which rare and uncommon variants (e.g., with a minor allele frequency <5%) contribute to glioma remains to be determined. However, two recent studies [7,8] provide the first evidence that this class of variants may contribute to 'missing heritability' [9] in glioma -one reporting the presumptive causal single nucleotide polymorphism (SNP) giving rise to the GWAS signal on chromosome 8 [7], and the other reporting a novel risk variant on chromosome 17 not previously implicated in GWASs [8]. Both of the novel variants identified in these studies were SNPs with minor allele frequencies of less than 5% and much higher relative risks than those found with common risk loci.…”

“…Through a series of investigations involving imputation of SNPs around the tagged locus, next-generation sequencing, and validation of the top candidate SNPs by custom genotyping in two independent series of cases and controls, Jenkins et al were able to narrow the search to a small region at the 8q24 locus with one SNP, rs55705857, producing the strongest signal [7]. When this SNP was included in models with other associated SNPs in the region, only the association of this SNP remained and the associations of the others became null, suggesting that rs55705857 is the cause of the association.…”