biostudies-literatureYanchus CCancer Research UKNHGRI NIH HHSNCI NIH HHSNINDS NIH HHSNIGMS NIH HHS68-78https://www.ebi.ac.uk/biostudies/studies/S-EPMC9926876biostudies-literatureUnknown378(6615)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%Science (New York, N.Y.)A noncoding single-nucleotide polymorphism at 8q24 drives &lt;i&gt;IDH1&lt;/i&gt;-mutant glioma formation.PMC9926876P50 CA097257P50 CA108961T32 NS082174R01 CA207360R01 CA052689DP2 GM149555U24 CA220242R01 HG003988R01 CA13902027603R01 CA230712R00 HG009682P30 CA015083R01 CA119215Visel ADickel DEYanchus CGosio JTSchramek DKollmeyer TMAhmed MWang LWinick-Ng WMalik ALiang MTsai RTaylor MDZadeh GDennis JWPawling JMaass PGDrucker KLMazrooei PWrana JMurphy DJHollingsworth EWCarson BMak TJiang LMichealraj KATrcka DHe HHLachance DHDirks PPennacchio LADe Lorenzo SBLupien MLowden CGeuenich MAl-Zahrani KNHernandez JJLoganathan SKWilson MDPombo AAli AJenkins RBAbyzov ABrowning JWLWiencke JZhou LElia AKosel MLAttisano LJacinto SBerman JPanda AEckel-Passow JECampbell KWrensch MKvon EZFortin JIda CMDecker PAfalseA noncoding single-nucleotide polymorphism at 8q24 drives &lt;i&gt;IDH1&lt;/i&gt;-mutant glioma formation.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%2022-01-01T00:00:00Z2022 Oct2025-08-13T03:04:25.592Z2025-02-19T03:27:05.849ZS-EPMC99268763620159010.1126/science.abj2890