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

Yanchus, C. et al. (2022) A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation. Science, 378(6615), pp. 68-78. (doi: 10.1126/science.abj2890) (PMID:36201590) (PMCID:PMC9926876)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Murphy, Professor Daniel
• Authors: 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.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Science
• Publisher: American Association for the Advancement of Science
• ISSN: 0036-8075
• ISSN (Online): 1095-9203
• Published Online: 06 October 2022