Epigenetic Aging Signatures Are Coherently Modified in Cancer

Abstract

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.

Author Summary

Our genome harbors epigenetic marks, such as DNA methylation (DNAm) at cytosine residues, which govern cellular differentiation. Some epigenetic modifications accumulate throughout life in a highly reproducible manner–they may contribute to the aging process and facilitate reliable age-predictions. So far, little is known how these “epigenetic aging signatures” are modified in cancer tissue and whether or not they are accelerated as compared to normal tissue. In this study, we systematically analyzed age-associated DNAm patterns in many types of cancer. In contrast to non-malignant tissue the epigenetic aging signatures hardly reflect chronological age of cancer patients. This may at least partially be attributed to the fact that cancer is a clonal disease capturing only the epigenetic make-up of the tumor-initiating cell. Notably, the aberrant DNAm patterns are not randomly distributed but reveal co-regulation at regions that become methylated upon aging in non-malignant tissue. Furthermore, we demonstrate that deviations of epigenetic age-predictions correlate with clinical parameters. In fact, they are clearly associated with overall survival in many types of cancer. These findings are particularly important, as they indicate relevance of age-associated DNA methylation patterns for malignant transformation, cancer development and prognosis.