PMID- 22346766
OWN - NLM
STAT- MEDLINE
DCOM- 20120518
LR  - 20220408
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Print)
IS  - 1553-7390 (Linking)
VI  - 8
IP  - 2
DP  - 2012 Feb
TI  - The dynamics and prognostic potential of DNA methylation changes at stem cell 
      gene loci in women's cancer.
PG  - e1002517
LID - 10.1371/journal.pgen.1002517 [doi]
LID - e1002517
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.
FAU - Zhuang, Joanna
AU  - Zhuang J
AD  - Department of Women's Cancer, University College London Elizabeth Garrett 
      Anderson Institute for Women's Health, London, UK.
FAU - Jones, Allison
AU  - Jones A
FAU - Lee, Shih-Han
AU  - Lee SH
FAU - Ng, Esther
AU  - Ng E
FAU - Fiegl, Heidi
AU  - Fiegl H
FAU - Zikan, Michal
AU  - Zikan M
FAU - Cibula, David
AU  - Cibula D
FAU - Sargent, Alexandra
AU  - Sargent A
FAU - Salvesen, Helga B
AU  - Salvesen HB
FAU - Jacobs, Ian J
AU  - Jacobs IJ
FAU - Kitchener, Henry C
AU  - Kitchener HC
FAU - Teschendorff, Andrew E
AU  - Teschendorff AE
FAU - Widschwendter, Martin
AU  - Widschwendter M
LA  - eng
GR  - Department of Health/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120209
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Polycomb-Group Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Repressor Proteins)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.- (TET1 protein, human)
SB  - IM
EIN - PLoS Genet. 2012 Mar;8(3). doi: 
      10.1371/annotation/35f168f3-c509-4b4f-b245-f6682325838e
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Cell Transformation, Neoplastic/*genetics
MH  - CpG Islands/genetics
MH  - DNA Methylation/*genetics
MH  - DNA-Binding Proteins/genetics
MH  - Embryonic Stem Cells/cytology/*metabolism
MH  - Epigenesis, Genetic
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Hematopoietic Stem Cells/cytology/metabolism
MH  - Humans
MH  - Middle Aged
MH  - Mixed Function Oxygenases
MH  - Neoplasms/*genetics/metabolism
MH  - Neoplastic Stem Cells/cytology/*metabolism
MH  - Polycomb-Group Proteins
MH  - *Prognosis
MH  - Promoter Regions, Genetic
MH  - Proto-Oncogene Proteins/genetics
MH  - Repressor Proteins/*genetics/metabolism
PMC - PMC3276553
COIS- The authors have declared that no competing interests exist.
EDAT- 2012/02/22 06:00
MHDA- 2012/05/19 06:00
PMCR- 2012/02/01
CRDT- 2012/02/21 06:00
PHST- 2011/10/14 00:00 [received]
PHST- 2011/12/15 00:00 [accepted]
PHST- 2012/02/21 06:00 [entrez]
PHST- 2012/02/22 06:00 [pubmed]
PHST- 2012/05/19 06:00 [medline]
PHST- 2012/02/01 00:00 [pmc-release]
AID - PGENETICS-D-11-02221 [pii]
AID - 10.1371/journal.pgen.1002517 [doi]
PST - ppublish
SO  - PLoS Genet. 2012 Feb;8(2):e1002517. doi: 10.1371/journal.pgen.1002517. Epub 2012 
      Feb 9.