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Sci Rep. 2016 Jun 10;6:27569. doi: 10.1038/srep27569.

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

Author information

1
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
2
Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Acibadem University, Istanbul, Turkey.
3
Department of Medical Biology, School of Medicine, Acibadem University, Istanbul, Turkey.
4
Izmir International Biomedicine and Genome Institute (iBG-izmir), Dokuz Eylul University, Izmir, Turkey.
5
Faculty of Engineering, Department of Medical Engineering, Acibadem University, Istanbul, Turkey.
6
Department of Biological Sciences and Bioengineering, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
7
Department of Neurosurgery, School of Medicine Yale University, New Haven, CT 06520, USA.
8
Functional Genomics Center Zurich, UZH/ETH, Zurich, Switzerland.
9
Cancer Institute, University College London, 72 Huntley Street, WC1E 6DD, London, UK.
10
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
11
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
12
Department of Medical Biochemistry, School of Medicine, Acibadem University, Istanbul, Turkey.
13
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
14
Department of Pathology, School of Medicine, Acibadem University, Istanbul, Turkey.
15
Department of Medical Statistics and Bioinformatics, School of Medicine, Acibadem University, Istanbul, Turkey.
16
Department of Neurosurgery, School of Medicine, Acibadem University, Istanbul, Turkey.

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.

PMID:
27282637
PMCID:
PMC4901315
DOI:
10.1038/srep27569
[Indexed for MEDLINE]
Free PMC Article

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