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

被引：43

作者：

Yanchus, Connor ^{[1
,2
,22
]}

Drucker, Kristen L. ^{[3
]}

Kollmeyer, Thomas M. ^{[3
]}

Tsai, Ricky ^{[1
]}

Winick-Ng, Warren ^{[4
]}

Liang, Minggao ^{[2
,5
]}

Malik, Ahmad ^{[1
,2
]}

Pawling, Judy ^{[1
]}

De Lorenzo, Silvana B. ^{[3
]}

Ali, Asma ^{[3
]}

Decker, Paul A. ^{[6
]}

Kosel, Matt L. ^{[6
]}

Panda, Arijit ^{[6
]}

Al-Zahrani, Khalid N. ^{[1
]}

Jiang, Lingyan ^{[1
]}

Browning, Jared W. L. ^{[2
,5
]}

Lowden, Chris ^{[1
]}

Geuenich, Michael ^{[1
,2
]}

Hernandez, J. Javier ^{[1
,2
]}

Gosio, Jessica T. ^{[1
,2
]}

Section, Musaddeque Ahmed ^{[5
,23
]}

Paragraph, Sampath Kumar Loganathan ^{[1
,24
]}

Berman, Jacob ^{[1
,25
]}

Trcka, Daniel ^{[1
]}

Michealraj, Kulandaimanuvel Antony ^{[5
,26
]}

Fortin, Jerome ^{[7
]}

Carson, Brittany ^{[1
,27
]}

Hollingsworth, Ethan W.

Jacinto, Sandra ^{[8
]}

Mazrooei, Parisa ^{[9
,28
]}

Zhou, Lily

Elia, Andrew

Lupien, Mathieu ^{[9
,10
]}

He, Housheng Hansen ^{[9
]}

Murphy, Daniel J.

Wang, Liguo

Abyzov, Alexej

Dennis, James W. ^{[1
]}

Maass, Philipp G. ^{[2
]}

Campbell, Kieran ^{[1
,2
]}

Wilson, Michael D. ^{[2
]}

Lachance, Daniel H. ^{[11
,12
,13
]}

Wrensch, Margaret ^{[14
]}

Wiencke, John ^{[14
]}

Mak, Tak ^{[7
,9
]}

Pennacchio, Len A. ^{[15
,16
,17
]}

Dickel, Diane E. ^{[15
,29
]}

Visel, Axel ^{[15
,17
,18
]}

Wrana, Jeffrey ^{[1
,2
]}

Taylor, Michael D. ^{[5
,9
]}

机构：

[1] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Ctr Mol & Syst Biol, Toronto, ON M5G 1X5, Canada

[2] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[3] Mayo Clin, Div Expt Pathol, Dept Lab Med & Pathol, Rochester, MN 55905 USA

[4] Berlin Inst Med Syst Biol, Epigenet Regulat & Chromatin Architecture Grp, Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany

[5] Hosp Sick Children, Toronto, ON M5G 1X8, Canada

[6] Mayo Clin, Dept Quantitat Hlth Sci, Rochester, MN 55905 USA

[7] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2C1, Canada

[8] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92617 USA

[9] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada

[10] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada

[11] Univ Glasgow, Inst Canc Sci, Glasgow G61 1BD, Lanark, Scotland

[12] Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland

[13] Mayo Clin, Dept Neurol & Lab Med & Pathol, Rochester, MN 55905 USA

[14] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA

[15] Lawrence Berkeley Natl Lab, Environm Genom & Syst Biol Div, Berkeley, CA 94710 USA

[16] Univ Calif Berkeley, Comparat Biochem Program, Berkeley, CA 94720 USA

[17] US Dept Energy Joint Genome Inst, Berkeley, CA 94720 USA

[18] Univ Calif Merced, Sch Nat Sci, Merced, CA 95343 USA

[19] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada

[20] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada

[21] Humboldt Univ, Inst Biol, D-10115 Berlin, Germany

[22] ArtisanBio, Toronto, ON M5G 1M1, Canada

[23] Hoffmann Roche Ltd, Computat Sci Exploratory Analyt, Roche Informat, Mississauga, ON L5N 5M8, Canada

[24] McGill Univ Hlth Ctr, Res Inst, Canc Res Program, Dept Otolaryngol Head & Neck Surg, Montreal, PQ, Canada

[25] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2C1, Canada

[26] Univ Pittsburgh, Sch Med, Dept Neurosurg, Pittsburgh, PA 15213 USA

[27] ApotheCom, New York, NY 10282 USA

[28] Genentech Inc, South San Francisco, CA 94080 USA

[29] Octant Inc, Emeryville, CA 94608 USA

来源：

SCIENCE | 2022年 / 378卷 / 6615期

关键词：

GENOME-WIDE ASSOCIATION; TERT PROMOTER MUTATIONS; NEURAL STEM-CELLS; TRANSCRIPTIONAL CONTROL; SUBVENTRICULAR ZONE; IDH; TUMORS; GLIOBLASTOMA; IDH1(R132H); LANDSCAPE;

D O I：

10.1126/science.abj2890

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 similar to 40% of LGG patients.

引用

页码：68 / 77

页数：10

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