The role of topological alterations in cancer

Chromosomal topology, the way DNA is folded in our cells, is emerging as an important regulator of enhancer-promoter interactions and gene regulation. During interphase, intrachromosomal interactions are governed by “topologically associating domains” (TADs) that facilitate frequent interactions within a domain, and minimize interactions between different domains. We have shown that in IDH mutated gliomas and in SDH deficient gastrointestinal stromal tumors, TAD insulation is being epigenetically perturbed to support oncogene activation. Specifically, we showed that CTCF binding sites are hyper-methylated and hence CTCF binding is blocked, leading to loss of insulation between super-enhancers and oncogenes, which promote oncogene over-expression. This raised the question whether altered topology is a more general mechanism of tumorigenesis. By combining epigenetic characterization with systematic analyses, we identify accumulating evidence of similar mechanisms in hepatocellular carcinoma, gastric adenocarcinoma and melanoma. Our findings reveal that epigenetic chromosomal topology aberrations is an important driver of cancer, that topological alterations can lead to dysregulation of multiple pathways synergistically promoting cancer, and suggest that epigenetics alone is able to drive tumorigenesis, without requiring genetic alterations.