Lupien, Mathieu
Mayo Clinic
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
Citations 1
A noncoding single-nucleotide polymorphism at 8q24 drives IDH1 -mutant glioma formation
Yanchus, Connor , Drucker, Kristen , Kollmeyer, Thomas M. , Tsai, Ricky , Winick‐Ng, Warren , Liang, Minggao , Malik, Ahmad , Pawling, Judy , Lorenzo, Silvana B. De, Ali, Asma, Decker, Paul A. , Kosel, Matt, Panda, Arijit , Al‐Zahrani, Khalid N. , Jiang, Lingyan , Browning, Jared , Lowden, Christopher , Hernández, J. Javier , Gosio, Jessica , Loganathan, Sampath K. , Berman, Jacob M. , Trcka, Daniel , Michealraj, Kulandaimanuvel Antony , Fortin, Jérôme, Carson, Brittany B. , Hollingsworth, Ethan W. , Jacinto, Sandra , Mazrooei, Parisa, Zhou, Lily , Elia, Andrew , Lupien, Mathieu , Murphy, Daniel J. , Wang, Liguo , Abyzov, Alexej , Dennis, James W. , Maass, Philipp G. , Wrensch, Margaret , Mak, Tak W. , Visel, Axel , Wrana, Jeffrey L. , Zadeh, Gelareh , Eckel‐Passow, Jeanette E. , Attisano, Liliana , Pombo, Ana , Kvon, Evgeny Z. , Jenkins, Robert B. , Schramek, Daniel , Drucker, Kristen L , De Lorenzo, Silvana B, Kosel, Matt L, Browning, Jared W L , Lowden, Chris , Hernandez, J Javier , Ahmed, Musaddeque , Loganathan, Sampath Kumar , Berman, Jacob , Trcka, Daniel , Hollingsworth, Ethan W , Elia, Andrew , Lupien, Mathieu , He, Housheng Hansen , Wang, Liguo , Abyzov, Alexej , Dennis, James W , Maass, Philipp G , Wilson, Michael D , Wrensch, Margaret , Mak, Tak , Pennacchio, Len A , Dickel, Diane E , Visel, Axel , Wrana, Jeffrey , Dirks, Peter , Eckel-Passow, Jeanette E , Attisano, Liliana , Pombo, Ana , Ida, Cristiane M , Kvon, Evgeny Z , Jenkins, RB , Schramek, Daniel , Kollmeyer, Thomas , Murphy, Daniel J , Decker, Paul A. , Kosel, Matthew , Geuenich, Michael J. , Ahmed, Musaddeque , He, Housheng Hansen , Campbell, Kieran R. , Wilson, Michael D. , Lachance, Daniel Honore , Wiencke, John K. , Taylor, Michael D. , Ida, Cristiane M.
Science | October 6, 2022 | Volume: 378 | Issue: 6615 | Pages: 68-78
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.