IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation
Akyerli, Cemaliye B.
Durasl, I. Melis
Henegariu, Octavian I.
Nanni, E. Paolo
Erson-Omay, E. Zeynep
Huse, Jason T.
Sav, M. Aydın
Sezerman, O. Uğur
Yaklcler, M. Cengiz
Pamir, M. Necmettin
- Journal Article
Rights / licenseCreative Commons Attribution 4.0 International
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. Show more
Journal / seriesScientific Reports
Pages / Article No.
PublisherNature Publishing Group
SubjectRare variants; Proteome informatics; Gene regulation; CNS cancer
Organisational unit02207 - Functional Genomics Center Zürich / Functional Genomics Center Zürich
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