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

Wenbing Xie, Ioannis Kagiampakis, Lixia Pan, Yang W. Zhang, Lauren Murphy, Yong Tao, Xiangqian Kong, Byunghak Kang, Limin Xia, Filipe L.F. Carvalho, Subhojit Sen, Ray Whay Chiu Yen, Cynthia A. Zahnow, Nita Ahuja, Stephen B. Baylin, Hariharan Easwaran

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)309-321.e5
JournalCancer cell
Volume33
Issue number2
DOIs
StatePublished - Feb 12 2018

Keywords

  • DNA methylation
  • aging
  • cancer
  • cancer risk
  • epigenetic
  • malignant transformation
  • oncogene-induced senescence
  • promoter CpG-island
  • senescence

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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