The role of mutation of metabolism-related genes in genomic hypermethylation

•Metabolic enzymes IDH, SDH, and FH are recurrent cancer drivers.•A consistent effect of these mutations is pervasive DNA hypermethylation.•This metabolic–epigenetic axis operates in diverse types of tumors.

Genetic mutations, metabolic dysfunction, and epigenetic misregulation are commonly considered to play distinct roles in tumor development and maintenance. However, intimate relationships between these mechanisms are now emerging. In particular, mutations in genes for the core metabolic enzymes IDH, SDH, and FH are significant drivers of diverse tumor types. In each case, the resultant accumulation of particular metabolites inhibits TET enzymes responsible for oxidizing 5-methylcytosine, leading to pervasive DNA hypermethylation.