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

Abstract

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 (<i>IDH)</i>-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 <i>Myc</i> promoter and increased <i>Myc</i> expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an <i>Idh1</i>^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.