1. A non-coding single nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
- Author
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Connor Yanchus, Kristen L. Drucker, Thomas M. Kollmeyer, Ricky Tsai, Minggao Liang, Lingyan Jiang, Judy Pawling, Asma Ali, Paul Decker, Matt Kosel, Arijit Panda, Ahmad Malik, Khalid N. Al-Zahrani, J. Javier Hernandez, Musaddeque Ahmed, Sampath Kumar Loganathan, Daniel Trcka, Antony Michaelraj, Jerome Fortin, Parisa Mazrooei, Lily Zhou, Andrew Elia, Mathieu Lupien, Housheng Hansen He, Liguo Wang, Alexej Abyzov, James W. Dennis, Michael D. Wilson, Jeffrey Wrana, Daniel Lachance, Margaret Wrensch, John Wiencke, Len A. Pennacchio, Diane E. Dickel, Axel Visel, Michael Taylor, Gelareh Zadeh, Peter Dirks, Jeanette E. Eckel-Passow, Tak Mak, Evgeny Kvon, Robert B. Jenkins, and Daniel Schramek
- Abstract
Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single nucleotide polymorphism rs55705857 (A>G), which confers a 6-fold increased risk of IDH-mutant low-grade glioma (LGG) and is amongst the highest genetic associations with cancer. By fine-mapping the locus, 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. To functionally test rs55705857, we generated an IDH1R132H-driven LGG mouse model and show that mutating the highly conserved, orthologous mouse rs55705857 locus dramatically accelerated tumor development from 463 to 172 days and increased penetrance from 30% to 75%. Overall, our work generates new LGG models and reveals mechanisms of the heritable predisposition to lethal glioma in ∼40% of LGG-patients.
- Published
- 2022