DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk

Overall shared DNA methylation patterns between senescence (Sen) and cancers have led to the model that tumor-promoting epigenetic patterns arise through senescence. We show that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence. Promoter hypermethylation events in transformation involve primarily pro-survival and developmental genes, similarly modified in primary tumors. Senescence-associated hypermethylation mainly involves metabolic regulators and appears early in proliferating “near-senescent” cells, which can be immortalized but are refractory to transformation. Importantly, a subset of transformation-associated hypermethylated developmental genes exhibits highest methylation gains at all age-associated cancer risk states across tissue types. These epigenetic changes favoring cell self-renewal and survival, arising during tissue aging, are fundamentally important for stratifying cancer risk and concepts for cancer prevention. Xie et al. show that transformation-associated methylation changes arise stochastically and evolve independently of senescence. A subset of transformation-associated hypermethylated genes favoring cell self-renewal and survival exhibits highest methylation gains during aging and early tumorigenesis.