IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation
IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation
Dosyalar
Tarih
2016-01-01
Yazarlar
Oktay, Yavuz
Ulgen, Ege
Can, Ozge
Akyerli, Cemaliye B.
Yuksel, Sirin
Erdemgil, Yigit
Durasi, I. Melis
Henegariu, Octavian Ioan
Nanni, E. Paolo
Selevsek, Nathalie
Süreli Yayın başlığı
Süreli Yayın ISSN
Cilt Başlığı
Yayınevi
NATURE PUBLISHING GROUP
Dergi Adı
SCIENTIFIC REPORTS
Özet
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.
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.