Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs.

ABSTRACT: Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood^1-3. A subset of gastrointestinal stromal tumours (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH) deficiency and global DNA hyper-methylation^4,5. 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 GIS

SUBMITTER: Flavahan WA 

PROVIDER: S-EPMC6913936 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature