A noncoding single-nucleotide polymorphism at 8q24 drives IDH1 -mutant glioma formation.
Connor YanchusKristen L DruckerThomas M KollmeyerRicky TsaiWarren Winick-NgMinggao LiangAhmad MalikJudy PawlingSilvana B De LorenzoAsma AliPaul A DeckerMatt L KoselArijit PandaKhalid N Al-ZahraniLingyan JiangJared W L BrowningChris LowdenMichael GeuenichJ Javier HernandezJessica T GosioMusaddeque AhmedSampath Kumar LoganathanJacob BermanDaniel TrckaKulandaimanuvel Antony MichealrajJerome FortinBrittany CarsonEthan W HollingsworthSandra JacintoParisa MazrooeiLily ZhouAndrew J EliaMathieu LupienHousheng Hansen HeDaniel J MurphyLiguo WangAlexej AbyzovJames W DennisPhilipp G MaassKieran CampbellMichael D WilsonDaniel H LachanceMargaret WrenschJohn WienckeTak Wah MakLen A PennacchioDiane E DickelAxel ViselJeffrey L WranaMichael D TaylorGelareh ZadehPeter B DirksJeanette E Eckel-PassowLiliana AttisanoAna PomboCristiane M IdaEvgeny Z KvonRobert B JenkinsDaniel SchramekPublished in: Science (New York, N.Y.) (2022)
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.
Keyphrases
- low grade
- wild type
- high grade
- transcription factor
- mouse model
- end stage renal disease
- binding protein
- newly diagnosed
- ejection fraction
- chronic kidney disease
- dna methylation
- peritoneal dialysis
- gene expression
- prognostic factors
- multiple sclerosis
- patient reported outcomes
- genome wide
- brain injury
- resting state
- cerebral ischemia
- single cell
- subarachnoid hemorrhage
- long non coding rna
- optic nerve