Abstract
The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17–16.52; 95% CI) for IDH-mutated gliomas and 12.85 (5.94–27.83; 95% CI) for IDH-mutated, 1p/19q co-deleted gliomas. Decreasing strength with increasing anaplasia implied a modulatory effect. No somatic mutations were noted at this locus in 114 blood-tumor pairs, nor was there a copy number difference between risk-allele and only-ancestral allele carriers. CCDC26 RNA-expression was rare and not different between the two groups. There were only minor subtype-specific differences in common glioma driver genes. RNA sequencing and LC-MS/MS comparisons pointed to significantly altered MYC-signaling. Baseline enhancer activity of the conserved region specifically on the MYC promoter and its further positive modulation by the SNP risk-allele was shown in vitro. Our findings implicate MYC deregulation as the underlying cause of the observed association.
Highlights
Single nucleotide polymorphisms (SNPs) at 8q24.21 have been associated with increased risk of IDH1/2-mutated gliomas[1,2,3]
Our study has three main findings: First, the rs55705857-associated glioma risk was confirmed in the Turkish population
The association was found to be unique to IDH-mutant gliomas
Summary
Table 2. rs55705857 is not associated with other IDH-mutant cancers. Upper panel: IDH-mutant tumor patients grouped according to type of tumor. Quantitative real-time PCR (qPCR) analysis with a TaqMan assay that targets the common exons (exons 3–4) of CCDC26 did not yield a significant difference between the G-allele carriers and non-carriers (1/10 vs 4/28 of samples with detectable expression, respectively; chi-square test p-value = 0.73) This result indicates that the G-allele is unlikely to exert its impact by altering CCDC26 expression. Neuronal progenitor cultured cells, a RNA-Pol[2] binding signal, and small RNA-seq data showing a balanced short RNA transcription, characteristic of enhancer-associated RNA (eRNA), a hallmark of active enhancers (Fig. 5a; Data obtained from the UCSC Genome Browser https://genome.ucsc.edu/) All these features suggest that rs55705857 may be a regulatory SNP, residing in a cancer-specific enhancer element. A more detailed and extensive analysis may be required to accurately measure the effect of rs55705857 on MYC expression
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