Altered chromosomal topology drives oncogenic programs in SDH-deficient GIST

AbstractEpigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood1–3. A subset of gastrointestinal stromal tumors (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,…

Abstract

Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood1–3. A subset of gastrointestinal stromal tumors (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 and strongly up-regulated 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 tumor, including hyper-methylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibitor, 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.

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Author information

Author notes

    • Yotam Drier

    Present address: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel

  1. These authors contributed equally: William A Flavahan, Yotam Drier.

Affiliations

  1. Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    • William A Flavahan
    • , Yotam Drier
    • , Sarah E. Johnstone
    • , Daniel R. Tarjan
    • , Esmat Hegazi
    • , Sarah J. Shareef
    • , Nauman M. Javed
    •  & Bradley E. Bernstein
  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • William A Flavahan
    • , Yotam Drier
    • , Sarah E. Johnstone
    • , Daniel R. Tarjan
    • , Esmat Hegazi
    • , Sarah J. Shareef
    • , Nauman M. Javed
    •  & Bradley E. Bernstein
  3. Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Matthew L. Hemming
    •  & George D. Demetri
  4. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School Boston, Boston, MA, USA

    • Matthew L. Hemming
    •  & George D. Demetri
  5. Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    • Chandrajit P. Raut
  6. Experimental Therapeutics Core, Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA

    • Benjamin K. Eschle
    •  & Prafulla C. Gokhale
  7. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    • Jason L. Hornick
  8. Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    • Ewa T. Sicinska
  9. Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA

    • George D. Demetri
    •  & Bradley E. Bernstein
  10. The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel

    • Yotam Drier

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Correspondence to
Yotam Drier or George D. Demetri or Bradley E. Bernstein.

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