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

Joanna Zhuang; Allison Jones; Shih Han Lee; Esther Ng; Heidi Fiegl; Michal Zikan; David Cibula; Alexandra Sargent; Helga B. Salvesen; Ian J. Jacobs; Henry C. Kitchener; Andrew E. Teschendorff; Martin Widschwendter

doi:10.1371/journal.pgen.1002517

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

Joanna Zhuang, Allison Jones, Shih Han Lee, Esther Ng, Heidi Fiegl, Michal Zikan, David Cibula, Alexandra Sargent, Helga B. Salvesen, Ian J. Jacobs, Henry C. Kitchener, Andrew E. Teschendorff, Martin Widschwendter

Research output: Contribution to journal › Article › peer-review

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. © 2012 Zhuang et al.

Original language	English
Article number	e1002517
Journal	PL o S Genetics
Volume	8
Issue number	2
DOIs	https://doi.org/10.1371/journal.pgen.1002517
Publication status	Published - Feb 2012

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1371/journal.pgen.1002517

http://www.plosgenetics.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pgen.1002517&representation=PDF

Cite this

Zhuang, J., Jones, A., Lee, S. H., Ng, E., Fiegl, H., Zikan, M., Cibula, D., Sargent, A., Salvesen, H. B., Jacobs, I. J., Kitchener, H. C., Teschendorff, A. E., & Widschwendter, M. (2012). The dynamics and prognostic potential of DNA methylation changes at stem cell gene loci in women's Cancer. PL o S Genetics, 8(2), Article e1002517. https://doi.org/10.1371/journal.pgen.1002517

@article{ece81f4603ba417492069814da334c3a,

title = "The dynamics and prognostic potential of DNA methylation changes at stem cell gene loci in women's Cancer",

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. {\textcopyright} 2012 Zhuang et al.",

author = "Joanna Zhuang and Allison Jones and Lee, {Shih Han} and Esther Ng and Heidi Fiegl and Michal Zikan and David Cibula and Alexandra Sargent and Salvesen, {Helga B.} and Jacobs, {Ian J.} and Kitchener, {Henry C.} and Teschendorff, {Andrew E.} and Martin Widschwendter",

note = ", Department of Health, United Kingdom",

year = "2012",

month = feb,

doi = "10.1371/journal.pgen.1002517",

language = "English",

volume = "8",

journal = "PL o S Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "2",

}

TY - JOUR

T1 - The dynamics and prognostic potential of DNA methylation changes at stem cell gene loci in women's Cancer

AU - Zhuang, Joanna

AU - Jones, Allison

AU - Lee, Shih Han

AU - Ng, Esther

AU - Fiegl, Heidi

AU - Zikan, Michal

AU - Cibula, David

AU - Sargent, Alexandra

AU - Salvesen, Helga B.

AU - Jacobs, Ian J.

AU - Kitchener, Henry C.

AU - Teschendorff, Andrew E.

AU - Widschwendter, Martin

N1 - , Department of Health, United Kingdom

PY - 2012/2

Y1 - 2012/2

N2 - 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. © 2012 Zhuang et al.

AB - 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. © 2012 Zhuang et al.

U2 - 10.1371/journal.pgen.1002517

DO - 10.1371/journal.pgen.1002517

M3 - Article

C2 - 22346766

SN - 1553-7390

VL - 8

JO - PL o S Genetics

JF - PL o S Genetics

IS - 2

M1 - e1002517

ER -

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

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this