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| Item Type: | Article |
|---|---|
| Title: | A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation |
| Creators: |
Yanchus, C.  ORCID: https://orcid.org/0000-0002-9450-7982, Drucker, K.L. ORCID: https://orcid.org/0000-0001-6244-5863, Kollmeyer, T.M. ORCID: https://orcid.org/0000-0002-0694-3224, Tsai, R. ORCID: https://orcid.org/0000-0001-5916-6978, Winick-Ng, W. ORCID: https://orcid.org/0000-0002-8716-5558, Liang, M. ORCID: https://orcid.org/0000-0002-4451-0921, Malik, A., Pawling, J. ORCID: https://orcid.org/0000-0003-3759-8555, De Lorenzo, S.B., Ali, A., Decker, P.A. ORCID: https://orcid.org/0000-0002-3756-4227, Kosel, M.L., Panda, A. ORCID: https://orcid.org/0000-0001-5156-6459, Al-Zahrani, K.N. ORCID: https://orcid.org/0000-0001-5771-7537, Jiang, L., Browning, J.W.L. ORCID: https://orcid.org/0000-0001-9938-7193, Lowden, C. ORCID: https://orcid.org/0000-0002-1839-164X, Geuenich, M., Hernandez, J.J. ORCID: https://orcid.org/0000-0001-6735-4303, Gosio, J.T., Ahmed, M. ORCID: https://orcid.org/0000-0002-5076-1102, Loganathan, S.K. ORCID: https://orcid.org/0000-0002-8809-1466, Berman, J. ORCID: https://orcid.org/0000-0001-6454-4996, Trcka, D. ORCID: https://orcid.org/0000-0002-2196-7160, Michealraj, K.A., Fortin, J., Carson, B., Hollingsworth, E.W. ORCID: https://orcid.org/0000-0002-5188-3929, Jacinto, S., Mazrooei, P., Zhou, L., Elia, A. ORCID: https://orcid.org/0000-0001-8619-1415, Lupien, M. ORCID: https://orcid.org/0000-0003-0929-9478, He, H.H. ORCID: https://orcid.org/0000-0003-2898-3363, Murphy, D.J., Wang, L. ORCID: https://orcid.org/0000-0003-2072-4826, Abyzov, A. ORCID: https://orcid.org/0000-0001-5405-6729, Dennis, J.W. ORCID: https://orcid.org/0000-0002-0295-5877, Maass, P.G. ORCID: https://orcid.org/0000-0002-2742-8301, Campbell, K., Wilson, M.D. ORCID: https://orcid.org/0000-0002-4015-3066, Lachance, D.H., Wrensch, M. ORCID: https://orcid.org/0000-0002-3070-7600, Wiencke, J., Mak, T. ORCID: https://orcid.org/0000-0001-6766-861X, Pennacchio, L.A. ORCID: https://orcid.org/0000-0002-8748-3732, Dickel, D.E. ORCID: https://orcid.org/0000-0001-5497-6824, Visel, A. ORCID: https://orcid.org/0000-0002-4130-7784, Wrana, J. ORCID: https://orcid.org/0000-0003-0932-0644, Taylor, M.D., Zadeh, G., Dirks, P. ORCID: https://orcid.org/0000-0001-5718-6465, Eckel-Passow, J.E. ORCID: https://orcid.org/0000-0002-6113-1114, Attisano, L. ORCID: https://orcid.org/0000-0003-4824-2642, Pombo, A. ORCID: https://orcid.org/0000-0002-7493-6288, Ida, C.M. ORCID: https://orcid.org/0000-0003-2768-2913, Kvon, E.Z. ORCID: https://orcid.org/0000-0002-1562-0945, Jenkins, R.B. ORCID: https://orcid.org/0000-0002-4049-694X and Schramek, D. ORCID: https://orcid.org/0000-0001-9977-2104
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| 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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