A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation

Item Type:	Article
Title:	A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
Creators Name:	Yanchus, C. and Drucker, K.L. and Kollmeyer, T.M. and Tsai, R. and Winick-Ng, W. and Liang, M. and Malik, A. and Pawling, J. and De Lorenzo, S.B. and Ali, A. and Decker, P.A. and Kosel, M.L. and Panda, A. and Al-Zahrani, K.N. and Jiang, L. and Browning, J.W.L. and Lowden, C. and Geuenich, M. and Hernandez, J.J. and Gosio, J.T. and Ahmed, M. and Loganathan, S.K. and Berman, J. and Trcka, D. and Michealraj, K.A. and Fortin, J. and Carson, B. and Hollingsworth, E.W. and Jacinto, S. and Mazrooei, P. and Zhou, L. and Elia, A. and Lupien, M. and He, H.H. and Murphy, D.J. and Wang, L. and Abyzov, A. and Dennis, J.W. and Maass, P.G. and Campbell, K. and Wilson, M.D. and Lachance, D.H. and Wrensch, M. and Wiencke, J. and Mak, T. and Pennacchio, L.A. and Dickel, D.E. and Visel, A. and Wrana, J. and Taylor, M.D. and Zadeh, G. and Dirks, P. and Eckel-Passow, J.E. and Attisano, L. and Pombo, A. and Ida, C.M. and Kvon, E.Z. and Jenkins, R.B. and Schramek, D.
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 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.
Keywords:	Brain Neoplasms, Glioma, Isocitrate Dehydrogenase, Mutation, Nucleotides, Animals, Mice
Source:	Science
ISSN:	0036-8075
Publisher:	American Association for the Advancement of Science
Volume:	378
Number:	6615
Page Range:	68-78
Date:	7 October 2022
Additional Information:	Copyright © 2022 the authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original US government works. https://www.science.org/about/science-licenses-journal-article-reuse
Official Publication:	https://doi.org/10.1126/science.abj2890
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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