作者
Connor Yanchus,Kristen L. Drucker,Thomas M. Kollmeyer,Ricky Tsai,Warren Winick-Ng,Minggao Liang,Ahmad Malik,Judy Pawling,Silvana B. De Lorenzo,Asma Ali,Paul A. Decker,Matt L. Kosel,Arijit Panda,Khalid N. Al-Zahrani,Lingyan Jiang,Jared W. L. Browning,Chris Lowden,Michael Geuenich,J. Javier Hernandez,Jessica T. Gosio,Musaddeque Ahmed,Sampath Kumar Loganathan,Jacob Berman,Daniel Trcka,Kulandaimanuvel Antony Michealraj,Jerome Fortin,Brittany Carson,Ethan W Hollingsworth,Sandra Jacinto,Parisa Mazrooei,Lily Zhou,Andrew J. Elia,Mathieu Lupien,Housheng Hansen He,Daniel J. Murphy,Liewei Wang,Alexej Abyzov,James W. Dennis,Philipp G. Maass,Kieran Campbell,Michael A. Wilson,Daniel H. Lachance,Margaret Wrensch,John Wiencke,Tak W. Mak,Len A. Pennacchio,Diane E. Dickel,Axel Visel,Jeffrey L. Wrana,Michael D. Taylor,Gelareh Zadeh,Peter B. Dirks,Jeanette E. Eckel-Passow,Liliana Attisano,Ana Pombo,Cristiane M. Ida,Evgeny Z. Kvon,Robert B. Jenkins,Daniel Schramek
摘要
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.