A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation

Science. 2022 Oct 7;378(6615):68-78. doi: 10.1126/science.abj2890. Epub 2022 Oct 6.


Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

MeSH terms

  • Animals
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / pathology
  • Chromosomes, Human, Pair 8* / genetics
  • Glioma* / genetics
  • Glioma* / pathology
  • Humans
  • Isocitrate Dehydrogenase* / genetics
  • Mice
  • Mutation
  • Polymorphism, Single Nucleotide


  • Isocitrate Dehydrogenase
  • IDH1 protein, human