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

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

Author information

1
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
2
Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
3
UM-DAE Center for Excellence in Basic Sciences (CBS), Mumbai University, Mumbai 400098, India.
4
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: sbaylin@jhmi.edu.
5
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: heaswar2@jhmi.edu.

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.

KEYWORDS:

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

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PMID:
29438699
PMCID:
PMC5813821
DOI:
10.1016/j.ccell.2018.01.008
[Indexed for MEDLINE]
Free PMC Article

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