The Dynamics and Prognostic Potential of DNA Methylation Changes at Stem Cell Gene Loci in Women's Cancer

• DOI: 10.1371/journal.pgen.1002517
• Publication Date: 2012-02-09T17:09:34Z
• Authors: 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. Teschen...; Martin Widschwendter
• Keywords: 0301 basic medicine; Polycomb-Group Proteins; cell transformation; QH426-470; Cell Transformation; polycomb group protein; gene targeting; Epigenesis, Genetic; Mixed Function Oxygenases; Neoplasms; middle aged; TET1 protein; 80 and over; genetics; Promoter Regions, Genetic; Aged, 80 and over; DNA methylation; adult; repressor protein; article; gene expression regulation; Middle Aged; Prognosis; 3. Good health; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; aged; female; Cell Transformation, Neoplastic; oncoprotein; Neoplastic Stem Cells; gynecologic cancer; Female; cancer invasion; carcinogenesis; Research Article; Adult; malignant transformation; cancer stem cell; 570; gene locus; 610; genetic epigenesis; Promoter Regions; 03 medical and health sciences; promoter region; Genetic; Proto-Oncogene Proteins; Genetics; metastasis; Humans; human; protein expression; Embryonic Stem Cells; Aged; Neoplastic; carcinoma in situ; DNA; prediction; DNA Methylation; Hematopoietic Stem Cells; embryonic stem cell; DNA binding protein; Repressor Proteins; Gene Expression Regulation; CpG island; cytology; hematopoietic stem cell; CpG Islands; prognosis; metabolism; neoplasm; Epigenesis

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.