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

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 Gosio; Musaddeque Ahmed; Sampath Kumar Loganathan; Jacob Berman; Daniel Trcka; Kulandaimanuvel Antony Michealraj; Jerome Fortin; Brittany Carson; Ethan 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 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

doi:10.1126/science.abj2890

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

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 GosioMusaddeque Ahmed, Sampath Kumar Loganathan, Jacob Berman, Daniel Trcka, Kulandaimanuvel Antony Michealraj, Jerome Fortin, Brittany Carson, Ethan 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 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	68-78
Number of pages	11
Journal	Science
Volume	378
Issue number	6615
DOIs	https://doi.org/10.1126/science.abj2890
State	Published - Oct 7 2022

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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., ... Schramek, D. (2022). A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation. Science, 378(6615), 68-78. https://doi.org/10.1126/science.abj2890

Yanchus, C, Drucker, KL, Kollmeyer, TM, Tsai, R, Winick-Ng, W, Liang, M, Malik, A, Pawling, J, De Lorenzo, SB, Ali, A, Decker, PA, Kosel, ML, Panda, A, Al-Zahrani, KN, Jiang, L, Browning, JWL, Lowden, C, Geuenich, M, Hernandez, JJ, Gosio, J, Ahmed, M, Kumar Loganathan, S, Berman, J, Trcka, D, Michealraj, KA, Fortin, J, Carson, B, Hollingsworth, E, Jacinto, S, Mazrooei, P, Zhou, L, Elia, A, Lupien, M, He, HH, Murphy, DJ, Wang, L , Abyzov, A, Dennis, JW, Maass, PG, Campbell, K, Wilson, MD, Lachance, DH, Wrensch, M, Wiencke, J, Mak, T, Pennacchio, LA, Dickel, D, Visel, A, Wrana, J, Taylor, MD, Zadeh, G, Dirks, P, Eckel-Passow, JE, Attisano, L, Pombo, A, Ida, CM, Kvon, EZ, Jenkins, RB & Schramek, D 2022, 'A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation', Science, vol. 378, no. 6615, pp. 68-78. https://doi.org/10.1126/science.abj2890

@article{cb3e906bdcd049ad8bde97717b10ce32,

title = "A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation",

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 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.",

author = "Connor Yanchus and Drucker, {Kristen L.} and Kollmeyer, {Thomas M.} and Ricky Tsai and Warren Winick-Ng and Minggao Liang and Ahmad Malik and Judy Pawling and {De Lorenzo}, {Silvana B.} and Asma Ali and Decker, {Paul A.} and Kosel, {Matt L.} and Arijit Panda and Al-Zahrani, {Khalid N.} and Lingyan Jiang and Browning, {Jared W.L.} and Chris Lowden and Michael Geuenich and Hernandez, {J. Javier} and Jessica Gosio and Musaddeque Ahmed and {Kumar Loganathan}, Sampath and Jacob Berman and Daniel Trcka and Michealraj, {Kulandaimanuvel Antony} and Jerome Fortin and Brittany Carson and Ethan Hollingsworth and Sandra Jacinto and Parisa Mazrooei and Lily Zhou and Andrew Elia and Mathieu Lupien and He, {Housheng Hansen} and Murphy, {Daniel J.} and Liguo Wang and Alexej Abyzov and Dennis, {James W.} and Maass, {Philipp G.} and Kieran Campbell and Wilson, {Michael D.} and Lachance, {Daniel H.} and Margaret Wrensch and John Wiencke and Tak Mak and Pennacchio, {Len A.} and Diane Dickel and Axel Visel and Jeffrey Wrana and Taylor, {Michael D.} and Gelareh Zadeh and Peter Dirks and Eckel-Passow, {Jeanette E.} and Liliana Attisano and Ana Pombo and Ida, {Cristiane M.} and Kvon, {Evgeny Z.} and Jenkins, {Robert B.} and Daniel Schramek",

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doi = "10.1126/science.abj2890",

language = "English (US)",

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T1 - A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation

AU - Yanchus, Connor

AU - Drucker, Kristen L.

AU - Kollmeyer, Thomas M.

AU - Tsai, Ricky

AU - Winick-Ng, Warren

AU - Liang, Minggao

AU - Malik, Ahmad

AU - Pawling, Judy

AU - De Lorenzo, Silvana B.

AU - Ali, Asma

AU - Decker, Paul A.

AU - Kosel, Matt L.

AU - Panda, Arijit

AU - Al-Zahrani, Khalid N.

AU - Jiang, Lingyan

AU - Browning, Jared W.L.

AU - Lowden, Chris

AU - Geuenich, Michael

AU - Hernandez, J. Javier

AU - Gosio, Jessica

AU - Ahmed, Musaddeque

AU - Kumar Loganathan, Sampath

AU - Berman, Jacob

AU - Trcka, Daniel

AU - Michealraj, Kulandaimanuvel Antony

AU - Fortin, Jerome

AU - Carson, Brittany

AU - Hollingsworth, Ethan

AU - Jacinto, Sandra

AU - Mazrooei, Parisa

AU - Zhou, Lily

AU - Elia, Andrew

AU - Lupien, Mathieu

AU - He, Housheng Hansen

AU - Murphy, Daniel J.

AU - Wang, Liguo

AU - Abyzov, Alexej

AU - Dennis, James W.

AU - Maass, Philipp G.

AU - Campbell, Kieran

AU - Wilson, Michael D.

AU - Lachance, Daniel H.

AU - Wrensch, Margaret

AU - Wiencke, John

AU - Mak, Tak

AU - Pennacchio, Len A.

AU - Dickel, Diane

AU - Visel, Axel

AU - Wrana, Jeffrey

AU - Taylor, Michael D.

AU - Zadeh, Gelareh

AU - Dirks, Peter

AU - Eckel-Passow, Jeanette E.

AU - Attisano, Liliana

AU - Pombo, Ana

AU - Ida, Cristiane M.

AU - Kvon, Evgeny Z.

AU - Jenkins, Robert B.

AU - Schramek, Daniel

PY - 2022/10/7

Y1 - 2022/10/7

N2 - 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.

AB - 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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JO - Science

JF - Science

IS - 6615

ER -

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

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