1. IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation
- Author
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Şirin Yüksel, I. Melis Durası, Sevin Turcan, Murat Gunel, Jason T. Huse, M. Necmettin Pamir, Cemaliye B Akyerli, E. Paolo Nanni, M. Cengiz Yakıcıer, Manu Gupta, Adrienne M. Flanagan, Nathalie Selevsek, M. Aydın Sav, Özge Can, Jonas Grossmann, O. Uğur Sezerman, Aysel Ozpinar, William Lee, E. Zeynep Erson-Omay, Yavuz Oktay, Hanwen Bai, Ege Ülgen, Yigit Erdemgil, Koray Özduman, Octavian Henegariu, Acibadem University Dspace, University of Zurich, and Özduman, Koray
- Subjects
Rare variants ,Proteome informatics ,Gene regulation ,CNS cancer ,0301 basic medicine ,Adult ,Male ,Proteomics ,Locus (genetics) ,Single-nucleotide polymorphism ,610 Medicine & health ,10071 Functional Genomics Center Zurich ,Kaplan-Meier Estimate ,Biology ,Polymorphism, Single Nucleotide ,Article ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Glioma ,medicine ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,Allele ,Enhancer ,Anaplasia ,Gene ,Alleles ,Genetic Association Studies ,Aged ,Genetics ,1000 Multidisciplinary ,Multidisciplinary ,Sequence Analysis, RNA ,Middle Aged ,medicine.disease ,Isocitrate Dehydrogenase ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Isocitrate dehydrogenase ,Mutation ,Cancer research ,570 Life sciences ,biology ,Female ,medicine.symptom ,Neoplasm Grading - 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., Scientific Reports, 6, ISSN:2045-2322
- Published
- 2016
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