Year: 2022
Type: article
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 IDH1 R132H -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.
Source: Science
Authors: Connor Yanchus, Kristen L. Drucker, Thomas M. Kollmeyer, Ricky Tsai, Warren Winick-Ng, Minggao Liang, Ahmad Malik, Judy Pawling, Silvana B. De Lorenzo, Asma Ali, Paul A. Decker, Matt L. Kosel, Arijit Panda, Khalid N. Al-Zahrani, Lingyan Jiang, Jared W. L. Browning, Chris Lowden, Michael Geuenich, J. Javier Hernandez, Jessica T. Gosio, Musaddeque Ahmed, Sampath Kumar Loganathan, Jacob Berman, Daniel Trcka, Kulandaimanuvel Antony Michealraj, Jerome Fortin, Brittany Carson, Ethan W. Hollingsworth, Sandra Jacinto, Parisa Mazrooei, Lily Zhou, Andrew Elia, Mathieu Lupien, Housheng Hansen He, Daniel J. Murphy, Liguo Wang, Alexej Abyzov, James W. Dennis, Philipp G. Maass, Kieran Campbell, Michael D. Wilson, Daniel H. Lachance, Margaret Wrensch, John Wiencke, Tak Mak, Len A. Pennacchio, Diane E. Dickel, Axel Visel, Jeffrey Wrana, Michael D. Taylor, Gelareh Zadeh, Peter Dirks, Jeanette E. Eckel-Passow, Liliana Attisano, Ana Pombo, Cristiane M. Ida, Evgeny Z. Kvon, Robert B. Jenkins, Daniel Schramek
Institutions: Mount Sinai Hospital, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Mayo Clinic, Max Delbrück Center, Hospital for Sick Children, University Health Network, Princess Margaret Cancer Centre, University of California, Irvine, Ontario Institute for Cancer Research, Cancer Research UK Scotland Institute, University of Glasgow, University of California, San Francisco, Lawrence Berkeley National Laboratory, Joint Genome Institute, University of California, Berkeley, University of California, Merced, Humboldt-Universität zu Berlin
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Energy, Mayo Clinic, National Brain Tumor Society, Ontario Institute for Cancer Research, Government of Ontario, Ting Tsung and Wei Fong Chao Family Foundation, Cancer Research UK, National Institutes of Health, University of California, San Francisco, Center for Individualized Medicine, Mayo Clinic, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Lawrence Berkeley National Laboratory
Awards: G1010341072, G1079818582, G1143651532, G1286236842, G1311563309, G1534123833, G179204697, Detection of somatic, subclonal and mosaic CNVs from sequencing, G22827645, G287561616, G3083819904, G3424261963, G382641700, G406789597, G42916606, G465867758, G4723022778, International Case Control Study of Malignant Glioma, Functional assessment of enhancer-gene interactions in vivo, G532587972, G534929556, Immune epigenetic biomarkers of survival in glioma epidemiology, G57785581, G6767173602, G7021921917, G7354628648, G9000045896, G9000074473, G9000105355, G9000108543, G9000146480, G9000344134, Drinking Water Treatment Laboratory and Tools, Mayo Clinic Comprehensive Cancer Center Support Grant, G969889393
OpenAlex ID: W4302425337