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Publication : A noncoding single-nucleotide polymorphism at 8q24 drives <i>IDH1</i>-mutant glioma formation.

First Author  Yanchus C Year  2022
Journal  Science Volume  378
Issue  6615 Pages  68-78
PubMed ID  36201590 Mgi Jnum  J:330279
Mgi Id  MGI:7367294 Doi  10.1126/science.abj2890
Citation  Yanchus C, et al. (2022) A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation. Science 378(6615):68-78
abstractText  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 Idh1(R132H)-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.
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