A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
In: Science, Jg. 378 (2022-10-07), Heft 6615
academicJournal
- 68 - 78
Zugriff:
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.
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A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
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Autor/in / Beteiligte Person: | 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 |
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Zeitschrift: | Science, Jg. 378 (2022-10-07), Heft 6615 |
Veröffentlichung: | eScholarship, University of California, 2022 |
Medientyp: | academicJournal |
Umfang: | 68 - 78 |
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