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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
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Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs
William A Flavahan1,2, Yotam Drier3,4,5, Sarah E Johnstone1,2
1Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Nature
|November 1, 2019
Summary
Epigenetic changes in gastrointestinal stromal tumors (GISTs) lacking mutations activate oncogenes by altering genome structure. This study identifies new therapeutic targets, particularly FGF receptor inhibitors, for these cancers.
Area of Science:
- Oncology
- Epigenetics
- Genomics
Background:
- Epigenetic aberrations are common in cancer but poorly understood.
- Some gastrointestinal stromal tumors (GISTs) with succinate dehydrogenase (SDH) deficiency exhibit global DNA hyper-methylation instead of kinase mutations.
Purpose of the Study:
- To investigate the mechanisms by which epigenetic alterations activate oncogenic programs in SDH-deficient GISTs.
- To map DNA methylation, CTCF insulators, enhancers, and chromosome topology in different GIST subtypes.
Main Methods:
- Systematic mapping of DNA methylation, CTCF insulators, enhancers, and chromosome topology.
- CRISPR-mediated gene editing in a GIST model.
- Establishment and analysis of a patient-derived xenograft (PDX) model.
Main Results:
- SDH-deficient GISTs show DNA methylation replacing CTCF binding at hundreds of insulators.
- Loss of a specific insulator in SDH-deficient GISTs alters genome topology, activating the FGF4 oncogene.
- A patient-derived xenograft model confirmed the epigenetic defects and sensitivity to FGFR and KIT inhibition.
Conclusions:
- Epigenetic alterations, including insulator defects and altered genome topology, can drive oncogenesis in GISTs lacking canonical mutations.
- These findings highlight novel therapeutic strategies targeting aberrant epigenetic pathways in GISTs, particularly using FGFR inhibitors.
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