A noncoding single-nucleotide polymorphism at 8q24 drives <i>IDH1</i> -mutant glioma formation-Reference-Cited by-同舟云学术

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

Published:2022-10-07 Issue:6615 Volume:378 Page:68-78
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Yanchus Connor¹²^ORCID,Drucker Kristen L.³^ORCID,Kollmeyer Thomas M.³^ORCID,Tsai Ricky¹^ORCID,Winick-Ng Warren⁴^ORCID,Liang Minggao²⁵^ORCID,Malik Ahmad¹²,Pawling Judy¹^ORCID,De Lorenzo Silvana B.³,Ali Asma³,Decker Paul A.⁶^ORCID,Kosel Matt L.⁶,Panda Arijit⁶^ORCID,Al-Zahrani Khalid N.¹^ORCID,Jiang Lingyan¹,Browning Jared W. L.²⁵^ORCID,Lowden Chris¹^ORCID,Geuenich Michael¹²,Hernandez J. Javier¹²^ORCID,Gosio Jessica T.¹²,Ahmed Musaddeque⁵^ORCID,Loganathan Sampath Kumar¹^ORCID,Berman Jacob¹^ORCID,Trcka Daniel¹^ORCID,Michealraj Kulandaimanuvel Antony⁵,Fortin Jerome⁷,Carson Brittany¹,Hollingsworth Ethan W.⁸^ORCID,Jacinto Sandra⁸,Mazrooei Parisa⁷⁹,Zhou Lily⁷,Elia Andrew⁷^ORCID,Lupien Mathieu⁷⁹¹⁰^ORCID,He Housheng Hansen⁷⁹^ORCID,Murphy Daniel J.¹¹¹²,Wang Liguo⁶^ORCID,Abyzov Alexej⁶^ORCID,Dennis James W.¹^ORCID,Maass Philipp G.²⁵^ORCID,Campbell Kieran¹²,Wilson Michael D.²⁵^ORCID,Lachance Daniel H.¹³,Wrensch Margaret¹⁴^ORCID,Wiencke John¹⁴,Mak Tak⁷⁹^ORCID,Pennacchio Len A.¹⁵¹⁶¹⁷^ORCID,Dickel Diane E.¹⁵^ORCID,Visel Axel¹⁵¹⁷¹⁸^ORCID,Wrana Jeffrey¹²^ORCID,Taylor Michael D.⁵⁹,Zadeh Gelareh⁵,Dirks Peter²⁵^ORCID,Eckel-Passow Jeanette E.⁶^ORCID,Attisano Liliana¹⁹²⁰^ORCID,Pombo Ana⁴²¹^ORCID,Ida Cristiane M.³^ORCID,Kvon Evgeny Z.⁸^ORCID,Jenkins Robert B.³^ORCID,Schramek Daniel¹²^ORCID

Affiliation:

1. Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.

2. Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.

3. Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.

4. Max-Delbrück Centre for Molecular Medicine, Berlin Institute for Medical Systems Biology, Epigenetic Regulation and Chromatin Architecture Group, 13092 Berlin, Germany.

5. Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

6. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA.

7. Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.

8. Department of Developmental and Cell Biology, University of California, Irvine, CA 92617, USA.

9. Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.

10. Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.

11. Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, Scotland, UK.

12. Cancer Research UK Beatson Institute, Glasgow G61 1BD, Scotland, UK.

13. Departments of Neurology and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.

14. Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.

15. Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94710, USA.

16. Comparative Biochemistry Program, University of California, Berkeley, CA 94720, USA.

17. US Department of Energy Joint Genome Institute, Berkeley, CA 94720, USA.

18. School of Natural Sciences, University of California, Merced, CA 95343, USA.

19. Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.

20. Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.

21. Institute of Biology, Humboldt University of Berlin, 10115 Berlin, Germany.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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3. Distinct germ line polymorphisms underlie glioma morphologic heterogeneity

4. A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation

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