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

Cancer Cell. 2018 Feb 12;33(2):309-321.e5. doi: 10.1016/j.ccell.2018.01.008.


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.

Keywords: DNA methylation; aging; cancer; cancer risk; epigenetic; malignant transformation; oncogene-induced senescence; promoter CpG-island; senescence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics*
  • Cellular Senescence / genetics
  • CpG Islands / genetics*
  • DNA Methylation / genetics*
  • Epigenesis, Genetic / genetics*
  • Humans
  • Mice
  • Mice, SCID
  • Neoplasms / genetics
  • Promoter Regions, Genetic / genetics
  • Risk