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Correlation of an epigenetic mitotic clock with cancer risk

Yang, Z; Wong, A; Kuh, D; Paul, DS; Rakyan, VK; Leslie, RD; Zheng, SC; ... Teschendorff, AE; + view all (2016) Correlation of an epigenetic mitotic clock with cancer risk. GENOME BIOLOGY , 17 (ARTN 205) 10.1186/s13059-016-1064-3. Green open access

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Abstract

Background - 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. Results - 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. Conclusions - 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.

Type: Article
Title: Correlation of an epigenetic mitotic clock with cancer risk
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/s13059-016-1064-3
Publisher version: http://dx.doi.org/10.1186/s13059-016-1064-3
Language: English
Additional information: © The Author(s). 2016
Keywords: Science & Technology, Life Sciences & Biomedicine, Biotechnology & Applied Microbiology, Genetics & Heredity, DNA methylation, Epigenetic clock, Cancer, Mitotic, Stem cells, Ageing, DETECTABLE CLONAL MOSAICISM, EPIGENOME-WIDE ASSOCIATION, STEM-CELL DIVISIONS, DNA METHYLATION, GENE-EXPRESSION, TELOMERE LENGTH, OVARIAN-CANCER, UNITED-STATES, ORAL-MUCOSA, AGE
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > MRC Unit for Lifelong Hlth and Ageing
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health > Womens Cancer
URI: https://discovery.ucl.ac.uk/id/eprint/1524662
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