IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation.
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.
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.|Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Acibadem University, Istanbul, Turkey.|Department of Medical Biology, School of Medicine, Acibadem University, Istanbul, Turkey.|Izmir International Biomedicine and Genome Institute (iBG-izmir), Dokuz Eylul University, Izmir, Turkey.
Yavuz
Y
Oktay
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
Ege
E
Ülgen
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.|Faculty of Engineering, Department of Medical Engineering, Acibadem University, Istanbul, Turkey.
Özge
Ö
Can
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.|Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Acibadem University, Istanbul, Turkey.|Department of Medical Biology, School of Medicine, Acibadem University, Istanbul, Turkey.
Cemaliye B
CB
Akyerli
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.|Department of Medical Biology, School of Medicine, Acibadem University, Istanbul, Turkey.
Şirin
Ş
Yüksel
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.
Yiğit
Y
Erdemgil
Department of Biological Sciences and Bioengineering, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
I Melis
IM
Durası
Department of Neurosurgery, School of Medicine Yale University, New Haven, CT 06520, USA.
Octavian Ioan
OI
Henegariu
Functional Genomics Center Zurich, UZH/ETH, Zurich, Switzerland.
E Paolo
EP
Nanni
Functional Genomics Center Zurich, UZH/ETH, Zurich, Switzerland.
Nathalie
N
Selevsek
Functional Genomics Center Zurich, UZH/ETH, Zurich, Switzerland.
Jonas
J
Grossmann
Department of Neurosurgery, School of Medicine Yale University, New Haven, CT 06520, USA.
E Zeynep
EZ
Erson-Omay
Department of Neurosurgery, School of Medicine Yale University, New Haven, CT 06520, USA.
Hanwen
H
Bai
Cancer Institute, University College London, 72 Huntley Street, WC1E 6DD, London, UK.
Manu
M
Gupta
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
William
W
Lee
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Şevin
Ş
Turcan
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.|Department of Medical Biochemistry, School of Medicine, Acibadem University, Istanbul, Turkey.
Aysel
A
Özpınar
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Jason T
JT
Huse
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.|Department of Pathology, School of Medicine, Acibadem University, Istanbul, Turkey.
M Aydın
MA
Sav
Cancer Institute, University College London, 72 Huntley Street, WC1E 6DD, London, UK.
Adrienne
A
Flanagan
Department of Neurosurgery, School of Medicine Yale University, New Haven, CT 06520, USA.
Murat
M
Günel
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.|Department of Medical Statistics and Bioinformatics, School of Medicine, Acibadem University, Istanbul, Turkey.
O Uğur
OU
Sezerman
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.|Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Acibadem University, Istanbul, Turkey.|Department of Medical Biology, School of Medicine, Acibadem University, Istanbul, Turkey.
M Cengiz
MC
Yakıcıer
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.|Department of Neurosurgery, School of Medicine, Acibadem University, Istanbul, Turkey.
M Necmettin
MN
Pamir
Brain Tumor Research Group, Acibadem University, Istanbul, Turkey.|Department of Neurosurgery, School of Medicine, Acibadem University, Istanbul, Turkey.
Koray
K
Özduman
D000328:Adult; D000368:Aged; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040901:Proteomics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D017423:Sequence Analysis, RNA
D014408:Biomarkers, Tumor; C489427:MYC protein, human; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D007521:Isocitrate Dehydrogenase