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.
authors.affiliation: Department of Women's Cancer, University College London Elizabeth Garrett Anderson Institute for Women's Health, London, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Zhuang
authors.forename: Allison
authors.initials: A
authors.lastname: Jones
authors.forename: Shih-Han
authors.initials: SH
authors.lastname: Lee
authors.forename: Esther
authors.initials: E
authors.lastname: Ng
authors.forename: Heidi
authors.initials: H
authors.lastname: Fiegl
authors.forename: Michal
authors.initials: M
authors.lastname: Zikan
authors.forename: David
authors.initials: D
authors.lastname: Cibula
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sargent
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jacobs
authors.forename: Henry C
authors.initials: HC
authors.lastname: Kitchener
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D006899:Mixed Function Oxygenases; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D063146:Polycomb-Group Proteins; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human