Oktay, YavuzUlgen, EgeCan, OzgeAkyerli, Cemaliye B.Yuksel, SirinErdemgil, YigitDurasi, I. MelisHenegariu, Octavian IoanNanni, E. PaoloSelevsek, NathalieGrossmann, JonasErson-Omay, E. ZeynepBai, HanwenGupta, ManuLee, WilliamTurcan, SevinOzpinar, AyselHuse, Jason T.Sav, M. AydinFlanagan, AdrienneGunel, MuratSezerman, O. UgurYakicier, M. CengizPamir, M. NecmettinOzduman, Koray2023-02-212023-02-212016-01-0110.1038/srep27569https://hdl.handle.net/11443/2618http://dx.doi.org/10.1038/srep27569The 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 (5.17-16.5295\% CI) for IDH-mutated gliomas and 12.85 (5.94-27.8395\% 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.ArticleWOS:000377694200001