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PreprintCited by 27Epigenetics and DNA MethylationCancer Genomics and DiagnosticsTelomeres, Telomerase, and Senescence

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An improved epigenetic counter to track mitotic age in normal and precancerous tissues

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Zhu, Tianyu, Tong, Huige, Du, Zhaozhen, Beck, Stephan, Teschendorff, Andrew E.·2023·Nature Communications
DOI 10.1101/2023.07.27.549809PMC PMC11101651

Preprint — published as 10.1038/s41467-024-48649-8 · Paper page

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Abstract

The cumulative number of stem cell divisions in a tissue, known as mitotic age, is thought to be a major determinant of cancer-risk. Somatic mutational and DNA methylation (DNAm) clocks are promising tools to molecularly track mitotic age, yet their relationship is underexplored and their potential for cancer risk prediction in normal tissues remains to be demonstrated. Here we build and validate an improved pan-tissue DNAm counter of total mitotic age called stemTOC. We demonstrate that stemTOC’s mitotic age proxy increases with the tumor cell-of-origin fraction in each of 15 cancer-types, in precancerous lesions, and in normal tissues exposed to major cancer risk factors. Extensive benchmarking against 6 other mitotic counters shows that stemTOC compares favorably, specially in the preinvasive and normal-tissue contexts. By cross-correlating stemTOC to two clock-like somatic mutational signatures, we confirm the mitotic-like nature of only one of these. Our data points towards DNAm as a promising molecular substrate for detecting mitotic-age increases in normal tissues and precancerous lesions, and hence for developing cancer-risk prediction strategies.

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Metadata

Authors
Zhu, T., Tong, H., Du, Z., Beck, S., & Teschendorff, A. E.
Affiliations
  • Shanghai Institute of Nutrition and Health (CN)
  • University College London (GB)
Corresponding author
Teschendorff, Andrew E.
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2023-07-29
Volume
15
Issue
1
Pages
4211-4211
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2023.07.27.549809
PMC
PMC11101651
OpenAlex
W4397022786
Cited by
27
References
1
Citations by year
2026: 14 · 2025: 12 · 2024: 1
FWCI
3.68
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (NSFC32370699, 32370699, 31970632, 32170652)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Keywords
DNA methylation clocks, somatic mutational signatures, cancer risk prediction, precancerous lesions, epigenetic aging, somatic mutations
MeSH terms
Humans, Mitosis, Mutation, Neoplasms, Precancerous Conditions, Stem Cells, DNA Methylation, Epigenesis, Genetic

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