IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation

Yavuz Oktay, Ege Ülgen, Özge Can, Cemaliye B. Akyerli, Şirin Yüksel, Yiǧit Erdemgil, I. Melis Durasl, Octavian Ioan Henegariu, E. Paolo Nanni, Nathalie Selevsek, Jonas Grossmann, E. Zeynep Erson-Omay, Hanwen Bai, Manu Gupta, William Lee, Şevin Turcan, Aysel Özplnar, Jason T. Huse, M. Aydln Sav, Adrienne FlanaganMurat Günel, O. Uǧur Sezerman, M. Cengiz Yaklcler, M. Necmettin Pamir, Koray Özduman

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29 Scopus citations

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.

Original languageEnglish
Article number27569
JournalScientific Reports
Volume6
DOIs
StatePublished - 10 Jun 2016
Externally publishedYes

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