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Published January 1, 2016 | Version v1
Journal article Open

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

Creators

  • 1. Acibadem Univ, Brain Tumor Res Grp, Istanbul, Turkey
  • 2. Sabanci Univ, Fac Engn & Nat Sci, Dept Biol Sci & Bioengn, Istanbul, Turkey
  • 3. Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT 06504 USA
  • 4. UZH ETH, Funct Genom Ctr Zurich, Zurich, Switzerland
  • 5. UCL, Canc Inst, 72 Huntley St, London WC1E 6DD, England
  • 6. Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10065 USA
  • 7. Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA
  • 8. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

Description

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.

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