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

• Published in: Scientific reports Vol. 6; no. 1; p. 27569
• Main Authors: Oktay, Yavuz, Ülgen, Ege, Can, Özge, Akyerli, Cemaliye B., Yüksel, Şirin, Erdemgil, Yiğit, Durası, İ. Melis, Henegariu, Octavian Ioan, Nanni, E. Paolo, Selevsek, Nathalie, Grossmann, Jonas, Erson-Omay, E. Zeynep, Bai, Hanwen, Gupta, Manu, Lee, William, Turcan, Şevin, Özpınar, Aysel, Huse, Jason T., Sav, M. Aydın, Flanagan, Adrienne, Günel, Murat, Sezerman, O. Uğur, Yakıcıer, M. Cengiz, Pamir, M. Necmettin, Özduman, Koray
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.06.2016; Nature Publishing Group
• Subjects: 13; 13/106; 38; 42/109; 45/23; 45/91; 631/114/2784; 631/208/200; 631/208/457/649/2219; 631/67/1922; 82/51; Brain cancer; Deregulation; Genotype & phenotype; Humanities and Social Sciences; Medicine; multidisciplinary; Mutants; Mutation; Neurosurgery; Patients; Population; Science; Science (multidisciplinary); Tumors; Istanbul Turkey; Turkey
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep27569

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.