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

  • Oktay Y Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
  • Ülgen E Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
  • Can Ö Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
  • Akyerli CB Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
  • Yüksel Ş Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
  • Erdemgil Y Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
  • Durası IM Department of Biological Sciences and Bioengineering, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
  • Henegariu OI Department of Neurosurgery, School of Medicine Yale University, New Haven, CT 06520, USA.
  • Nanni EP Functional Genomics Center Zurich, UZH/ETH, Zurich, Switzerland.
  • Selevsek N Functional Genomics Center Zurich, UZH/ETH, Zurich, Switzerland.
  • Grossmann J Functional Genomics Center Zurich, UZH/ETH, Zurich, Switzerland.
  • Erson-Omay EZ Department of Neurosurgery, School of Medicine Yale University, New Haven, CT 06520, USA.
  • Bai H Department of Neurosurgery, School of Medicine Yale University, New Haven, CT 06520, USA.
  • Gupta M Cancer Institute, University College London, 72 Huntley Street, WC1E 6DD, London, UK.
  • Lee W Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Turcan Ş Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Özpınar A Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
  • Huse JT Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Sav MA Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
  • Flanagan A Cancer Institute, University College London, 72 Huntley Street, WC1E 6DD, London, UK.
  • Günel M Department of Neurosurgery, School of Medicine Yale University, New Haven, CT 06520, USA.
  • Sezerman OU Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
  • Yakıcıer MC Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
  • Pamir MN Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
  • Özduman K Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
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  • 2016-06-11
Published in:
  • Scientific reports. - 2016
Adult
Aged
Alleles
Biomarkers, Tumor
Female
Gene Expression Regulation, Neoplastic
Genetic Association Studies
Genetic Predisposition to Disease
Glioma
Humans
Isocitrate Dehydrogenase
Kaplan-Meier Estimate
Male
Middle Aged
Mutation
Neoplasm Grading
Neoplasm Proteins
Polymorphism, Single Nucleotide
Proteomics
Proto-Oncogene Proteins c-myc
Sequence Analysis, RNA
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/254002
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