Succinate dehydrogenase-deficient gastrointestinal stromal tumors have altered genome topology.
Major Finding: Succinate dehydrogenase-deficient gastrointestinal stromal tumors have altered genome topology.
Mechanism: Hypermethylation at insulating CTCF binding sites causes aberrant superenhancer–oncogene contact.
Impact: This study identifies a previously unknown driving mechanism and demonstrates its relevance in mice.
Gastrointestinal stromal tumors (GIST) are usually driven by mutations in either the KIT or PDGFRA receptor tyrosine kinases (RTK), but some instead have loss of succinate dehydrogenase (SDH), which is associated with DNA hypermethylation. Flavahan, Drier, and colleagues found that DNA hypermethylation in SDH-deficient GIST leads to alterations in genome topology that trigger activation of non-mutated proto-oncogenes. Chromatin immunoprecipitation and sequencing experiments revealed that 5% of binding sites for the transcription factor CTCF were lost in SDH-deficient GIST compared with mutant TKI-driven GIST, and these sites had greatly increased DNA methylation. Mapping of topologically associating domain (TAD) boundaries along with enhancer mapping and analysis of gene-expression data showed that among these sites, 60 were CTCF loop anchors that would otherwise have prevented contact between superenhancers and specific genes. Notably, one such missing TAD boundary would normally prevent contact between a superenhancer and the oncogenes FGF3 and FGF4, and FGF3 and FGF4 expression were increased 6-fold and 35-fold, respectively, in SDH-deficient GIST. Similar results were observed with the wild-type KIT proto-oncogene. Further, experiments using a GIST-derived cell line in which the two CTCF binding sites that normally insulate FGF4 from the superenhancer were edited indicated increased contact between the superenhancer and FGF4 as well as increased FGF4 expression in this context. These results imply that the loss of these CTCF binding sites is directly responsible for the topological changes around FGF4 and the associated increase in FGF4 expression seen in SDH-deficient GISTs. In a new patient-derived xenograft mouse model of SDH-deficient GIST, treatment with a KIT inhibitor somewhat suppressed tumor growth, treatment with an FGFR inhibitor substantially reduced tumor growth, and combined treatment resulted in even greater suppression of tumor growth, implying functional significance for the observed epigenetic alterations. Collectively, these findings identify a possible driving mechanism behind SDH-deficient GIST oncogenesis and tumor maintenance and provide a proof of concept for treatment of this subset of GISTs with FGFR and KIT inhibitors.
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