title: Correlation of an epigenetic mitotic clock with cancer risk.
abstract: Variation in cancer risk among somatic tissues has been attributed to variations in the underlying rate of stem cell division. For a given tissue type, variable cancer risk between individuals is thought to be influenced by extrinsic factors which modulate this rate of stem cell division. To date, no molecular mitotic clock has been developed to approximate the number of stem cell divisions in a tissue of an individual and which is correlated with cancer risk.
  
  
  
  Here, we integrate mathematical modeling with prior biological knowledge to construct a DNA methylation-based age-correlative model which approximates a mitotic clock in both normal and cancer tissue. By focusing on promoter CpG sites that localize to Polycomb group target genes that are unmethylated in 11 different fetal tissue types, we show that increases in DNA methylation at these sites defines a tick rate which correlates with the estimated rate of stem cell division in normal tissues. Using matched DNA methylation and RNA-seq data, we further show that it correlates with an expression-based mitotic index in cancer tissue. We demonstrate that this mitotic-like clock is universally accelerated in cancer, including pre-cancerous lesions, and that it is also accelerated in normal epithelial cells exposed to a major carcinogen.
  
  
  
  Unlike other epigenetic and mutational clocks or the telomere clock, the epigenetic clock proposed here provides a concrete example of a mitotic-like clock which is universally accelerated in cancer and precancerous lesions.
authors.affiliation: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, 320 Yue Yang Road, Shanghai, 200031, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: MRC Unit for Lifelong Health and Ageing at University College London, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wong
authors.affiliation: MRC Unit for Lifelong Health and Ageing at University College London, London, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Kuh
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
authors.forename: Dirk S
authors.initials: DS
authors.lastname: Paul
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.
authors.forename: Vardhman K
authors.initials: VK
authors.lastname: Rakyan
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.
authors.forename: R David
authors.initials: RD
authors.lastname: Leslie
authors.affiliation: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, 320 Yue Yang Road, Shanghai, 200031, China.
authors.forename: Shijie C
authors.initials: SC
authors.lastname: Zheng
authors.affiliation: Department of Women's Cancer, University College London, 74 Huntley Street, London, WC1E 6AU, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, 320 Yue Yang Road, Shanghai, 200031, China. a.teschendorff@ucl.ac.uk.|Department of Women's Cancer, University College London, 74 Huntley Street, London, WC1E 6AU, UK. a.teschendorff@ucl.ac.uk.|Statistical Cancer Genomics, Paul O'Gorman Building, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK. a.teschendorff@ucl.ac.uk.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D008940:Mitotic Index; D008962:Models, Theoretical; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology; D063146:Polycomb-Group Proteins / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D063146:Polycomb-Group Proteins
keywords: Ageing; Cancer; DNA methylation; Epigenetic clock; Mitotic; Stem cells