Compromised epigenetic robustness in cancer: fueling evolution, exposing weakness.

The complex network of proteins that regulate chromatin and DNA methylation landscapes is often disrupted in cancer. Clonal and subclonal mutations targeting a wide range of molecular functions are frequently observed across cancer types, and emerging evidence suggests that loss of robust epigenetic control promotes both cancer initiation and evolution, independently of context-specific effects. Here, we review how diverse genetic alterations that destabilize the epigenetic regulatory network (ERN) may converge into common phenotypes. We also discuss the implications of altered network topology and systemic epigenetic disorder for the evolution, vulnerability, and therapeutic resistance of cancers.