학술논문
A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
Document Type
article
Author
Yanchus, Connor; Drucker, Kristen L; Kollmeyer, Thomas M; Tsai, Ricky; Winick-Ng, Warren; Liang, Minggao; Malik, Ahmad; Pawling, Judy; De Lorenzo, Silvana B; Ali, Asma; Decker, Paul A; Kosel, Matt L; Panda, Arijit; Al-Zahrani, Khalid N; Jiang, Lingyan; Browning, Jared WL; Lowden, Chris; Geuenich, Michael; Hernandez, J Javier; Gosio, Jessica T; Ahmed, Musaddeque; Loganathan, Sampath Kumar; Berman, Jacob; Trcka, Daniel; Michealraj, Kulandaimanuvel Antony; Fortin, Jerome; Carson, Brittany; Hollingsworth, Ethan W; Jacinto, Sandra; Mazrooei, Parisa; Zhou, Lily; Elia, Andrew; Lupien, Mathieu; He, Housheng Hansen; Murphy, Daniel J; Wang, Liguo; Abyzov, Alexej; Dennis, James W; Maass, Philipp G; Campbell, Kieran; Wilson, Michael D; Lachance, Daniel H; Wrensch, Margaret; Wiencke, John; Mak, Tak; Pennacchio, Len A; Dickel, Diane E; Visel, Axel; Wrana, Jeffrey; Taylor, Michael D; Zadeh, Gelareh; Dirks, Peter; Eckel-Passow, Jeanette E; Attisano, Liliana; Pombo, Ana; Ida, Cristiane M; Kvon, Evgeny Z; Jenkins, Robert B; Schramek, Daniel
Source
Science. 378(6615)
Subject
Language
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 (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 Idh1R132H-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.