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The dynamics and prognostic potential of DNA methylation changes at stem cell gene loci in women's cancer.

Zhuang, J; Jones, A; Lee, SH; Ng, E; Fiegl, H; Zikan, M; Cibula, D; ... Widschwendter, M; + view all (2012) The dynamics and prognostic potential of DNA methylation changes at stem cell gene loci in women's cancer. PLoS Genetics , 8 (2) , Article e1002517. 10.1371/journal.pgen.1002517. Green open access

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Abstract

Aberrant DNA methylation is an important cancer hallmark, yet the dynamics of DNA methylation changes in human carcinogenesis remain largely unexplored. Moreover, the role of DNA methylation for prediction of clinical outcome is still uncertain and confined to specific cancers. Here we perform the most comprehensive study of DNA methylation changes throughout human carcinogenesis, analysing 27,578 CpGs in each of 1,475 samples, ranging from normal cells in advance of non-invasive neoplastic transformation to non-invasive and invasive cancers and metastatic tissue. We demonstrate that hypermethylation at stem cell PolyComb Group Target genes (PCGTs) occurs in cytologically normal cells three years in advance of the first morphological neoplastic changes, while hypomethylation occurs preferentially at CpGs which are heavily Methylated in Embryonic Stem Cells (MESCs) and increases significantly with cancer invasion in both the epithelial and stromal tumour compartments. In contrast to PCGT hypermethylation, MESC hypomethylation progresses significantly from primary to metastatic cancer and defines a poor prognostic signature in four different gynaecological cancers. Finally, we associate expression of TET enzymes, which are involved in active DNA demethylation, to MESC hypomethylation in cancer. These findings have major implications for cancer and embryonic stem cell biology and establish the importance of systemic DNA hypomethylation for predicting prognosis in a wide range of different cancers.

Type: Article
Title: The dynamics and prognostic potential of DNA methylation changes at stem cell gene loci in women's cancer.
Location: US
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1002517
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1002517
Language: English
Additional information: © 2012 Zhuang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3276553
Keywords: Adult, Aged, Aged, 80 and over, Cell Transformation, Neoplastic, CpG Islands, DNA Methylation, DNA-Binding Proteins, Embryonic Stem Cells, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Hematopoietic Stem Cells, Humans, Middle Aged, Neoplasms, Neoplastic Stem Cells, Polycomb-Group Proteins, Prognosis, Promoter Regions, Genetic, Proto-Oncogene Proteins, Repressor Proteins
UCL classification: 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 Pop Health Sciences > Inst for Women's Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Inst for Women's Health > Women's Cancer
URI: https://discovery.ucl.ac.uk/id/eprint/1340529
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