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

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.异常DNA甲基化是重要的癌症标志特征之一，然而人类癌变过程中DNA甲基化变化的动态调控机制仍未得到充分阐明。此外，DNA甲基化在临床结局预测中的作用仍不明确，且仅局限于特定癌种。本研究开展了目前最为全面的人类癌变全程DNA甲基化变化分析，对1475份样本中的每份样本均检测了27578个CpG位点，样本覆盖范围从非侵袭性肿瘤转化前的正常细胞，延伸至非侵袭性、侵袭性肿瘤及转移组织。研究发现，干细胞多梳家族靶基因（PolyComb Group Target genes, PCGTs）的高甲基化可在首次出现形态学肿瘤病变前3年，于细胞学形态正常的细胞中被检出；而低甲基化则优先发生于胚胎干细胞高甲基化CpG位点（MESCs），且在肿瘤上皮与间质微环境中均随肿瘤侵袭程度的升高而显著增强。与PCGT高甲基化不同，MESCs低甲基化可随肿瘤从原发灶进展至转移灶而显著加剧，并在四种不同妇科恶性肿瘤中构成不良预后特征。最后，本研究将参与主动DNA去甲基化过程的TET酶（TET enzymes）的表达水平，与癌症中的MESCs低甲基化建立了关联。上述研究发现对癌症及胚胎干细胞生物学领域具有重要价值，并证实了系统性DNA低甲基化在多种不同癌种的预后预测中的关键意义。