Author
Listed:
- William A. Flavahan
(Massachusetts General Hospital and Harvard Medical School
Broad Institute of MIT and Harvard)
- Yotam Drier
(Massachusetts General Hospital and Harvard Medical School
Broad Institute of MIT and Harvard
The Hebrew University)
- Sarah E. Johnstone
(Massachusetts General Hospital and Harvard Medical School
Broad Institute of MIT and Harvard)
- Matthew L. Hemming
(Dana-Farber Cancer Institute
Dana-Farber Cancer Institute and Harvard Medical School Boston)
- Daniel R. Tarjan
(Massachusetts General Hospital and Harvard Medical School
Broad Institute of MIT and Harvard)
- Esmat Hegazi
(Massachusetts General Hospital and Harvard Medical School
Broad Institute of MIT and Harvard)
- Sarah J. Shareef
(Massachusetts General Hospital and Harvard Medical School
Broad Institute of MIT and Harvard)
- Nauman M. Javed
(Massachusetts General Hospital and Harvard Medical School
Broad Institute of MIT and Harvard)
- Chandrajit P. Raut
(Brigham and Women’s Hospital and Harvard Medical School)
- Benjamin K. Eschle
(Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute)
- Prafulla C. Gokhale
(Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute)
- Jason L. Hornick
(Brigham and Women’s Hospital and Harvard Medical School)
- Ewa T. Sicinska
(Dana-Farber Cancer Institute and Harvard Medical School)
- George D. Demetri
(Dana-Farber Cancer Institute
Dana-Farber Cancer Institute and Harvard Medical School Boston
Harvard Medical School)
- Bradley E. Bernstein
(Massachusetts General Hospital and Harvard Medical School
Broad Institute of MIT and Harvard
Harvard Medical School)
Abstract
Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood1–3. A subset of gastrointestinal stromal tumours (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH) deficiency and global DNA hyper-methylation4,5. Here, we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary between enhancer and oncogene, and strongly upregulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetics of the parental tumour, including hypermethylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibition, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers.
Suggested Citation
William A. Flavahan & Yotam Drier & Sarah E. Johnstone & Matthew L. Hemming & Daniel R. Tarjan & Esmat Hegazi & Sarah J. Shareef & Nauman M. Javed & Chandrajit P. Raut & Benjamin K. Eschle & Prafulla , 2019.
"Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs,"
Nature, Nature, vol. 575(7781), pages 229-233, November.
Handle:
RePEc:nat:nature:v:575:y:2019:i:7781:d:10.1038_s41586-019-1668-3
DOI: 10.1038/s41586-019-1668-3
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Cited by:
- Brent S. Perlman & Noah Burget & Yeqiao Zhou & Gregory W. Schwartz & Jelena Petrovic & Zora Modrusan & Robert B. Faryabi, 2024.
"Enhancer-promoter hubs organize transcriptional networks promoting oncogenesis and drug resistance,"
Nature Communications, Nature, vol. 15(1), pages 1-21, December.
- Konstantin Okonechnikov & Aylin Camgöz & Owen Chapman & Sameena Wani & Donglim Esther Park & Jens-Martin Hübner & Abhijit Chakraborty & Meghana Pagadala & Rosalind Bump & Sahaana Chandran & Katerina K, 2023.
"3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma,"
Nature Communications, Nature, vol. 14(1), pages 1-16, December.
- Xiaojing Wang & Anne-Marie Langevin & Peter J. Houghton & Siyuan Zheng, 2022.
"Genomic disparities between cancers in adolescent and young adults and in older adults,"
Nature Communications, Nature, vol. 13(1), pages 1-16, December.
- Judith H. I. Haarhuis & Robin H. Weide & Vincent A. Blomen & Koen D. Flach & Hans Teunissen & Laureen Willems & Thijn R. Brummelkamp & Benjamin D. Rowland & Elzo Wit, 2022.
"A Mediator-cohesin axis controls heterochromatin domain formation,"
Nature Communications, Nature, vol. 13(1), pages 1-10, December.
- Katelyn L. Mortenson & Courtney Dawes & Emily R. Wilson & Nathan E. Patchen & Hailey E. Johnson & Jason Gertz & Swneke D. Bailey & Yang Liu & Katherine E. Varley & Xiaoyang Zhang, 2024.
"3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression,"
Nature Communications, Nature, vol. 15(1), pages 1-15, December.
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