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

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Item Type:	Article
Title:	A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
Creators Name:	Yanchus, C., Drucker, K.L., Kollmeyer, T.M., Tsai, R., Winick-Ng, W., Liang, M., Malik, A., Pawling, J., De Lorenzo, S.B., Ali, A., Decker, P.A., Kosel, M.L., Panda, A., Al-Zahrani, K.N., Jiang, L., Browning, J.W.L., Lowden, C., Geuenich, M., Hernandez, J.J., Gosio, J.T., Ahmed, M., Loganathan, S.K., Berman, J., Trcka, D., Michealraj, K.A., Fortin, J., Carson, B., Hollingsworth, E.W., Jacinto, S., Mazrooei, P., Zhou, L., Elia, A., Lupien, M., He, H.H., Murphy, D.J., Wang, L., Abyzov, A., Dennis, J.W., Maass, P.G., Campbell, K., Wilson, M.D., Lachance, D.H., Wrensch, M., Wiencke, J., Mak, T., Pennacchio, L.A., Dickel, D.E., Visel, A., Wrana, J., Taylor, M.D., Zadeh, G., Dirks, P., Eckel-Passow, J.E., Attisano, L., Pombo, A., Ida, C.M., Kvon, E.Z., 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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