Epigenetic Aging Signatures Are Coherently Modified in Cancer

PLoS Genet. 2015 Jun 25;11(6):e1005334. doi: 10.1371/journal.pgen.1005334. eCollection 2015 Jun.


Aging is associated with highly reproducible DNA methylation (DNAm) changes, which may contribute to higher prevalence of malignant diseases in the elderly. In this study, we analyzed epigenetic aging signatures in 5,621 DNAm profiles of 25 cancer types from The Cancer Genome Atlas (TCGA). Overall, age-associated DNAm patterns hardly reflect chronological age of cancer patients, but they are coherently modified in a non-stochastic manner, particularly at CpGs that become hypermethylated upon aging in non-malignant tissues. This coordinated regulation in epigenetic aging signatures can therefore be used for aberrant epigenetic age-predictions, which facilitate disease stratification. For example, in acute myeloid leukemia (AML) higher epigenetic age-predictions are associated with increased incidence of mutations in RUNX1, WT1, and IDH2, whereas mutations in TET2, TP53, and PML-PARA translocation are more frequent in younger age-predictions. Furthermore, epigenetic aging signatures correlate with overall survival in several types of cancer (such as lower grade glioma, glioblastoma multiforme, esophageal carcinoma, chromophobe renal cell carcinoma, cutaneous melanoma, lung squamous cell carcinoma, and neuroendocrine neoplasms). In conclusion, age-associated DNAm patterns in cancer are not related to chronological age of the patient, but they are coordinately regulated, particularly at CpGs that become hypermethylated in normal aging. Furthermore, the apparent epigenetic age-predictions correlate with clinical parameters and overall survival in several types of cancer, indicating that regulation of DNAm patterns in age-associated CpGs is relevant for cancer development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / genetics*
  • CpG Islands
  • DNA Methylation
  • Databases, Genetic
  • Epigenesis, Genetic*
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / mortality
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / mortality
  • Male
  • Middle Aged
  • Mutation
  • Neoplasms / genetics*
  • Neoplasms / mortality
  • Prognosis
  • Reference Values

Associated data

  • GEO/GSE40279

Grant support

This work was supported by the Else Kröner-Fresenius Stiftung, the German Research Foundation (WA/1706/2-1), the Federal Ministry for Education and Research (BMBF:01KU1402B), and the Interdisciplinary Center for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (O1-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.