01Beyond DNA sequence
Epigenetics changes gene activity without altering sequence. Cancer genomes typically show global hypomethylation (destabilizing chromosomes and activating repeats) alongside local hypermethylation of CpG-island promoters, silencing tumor suppressors like MLH1, p16 and BRCA1.
Histone modifications also shift: losing acetylation compacts chromatin and silences genes.
02Mutated chromatin machinery
Many tumors mutate the epigenetic machinery itself — EZH2, ARID1A, DNMT3A and TET2. In gliomas and AML, mutant IDH1/2 makes the 'oncometabolite' 2-hydroxyglutarate, which blocks demethylases and causes widespread hypermethylation.
Because epigenetic marks are reversible, they're drug targets: DNMT inhibitors (azacitidine) and HDAC inhibitors (vorinostat) treat certain blood cancers, and IDH inhibitors (ivosidenib) are approved.