Center for Epigenetics and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Intern Med. 2014 Jul;276(1):5-11. doi: 10.1111/joim.12224.
The aim of this review is to summarize an evolution of thinking about the epigenetic basis of human cancer, from the earliest studies of altered DNA methylation in cancer to the modern comprehensive epigenomic era. Converging data from epigenetic studies of primary cancers and from experimental studies of chromatin in development and epithelial-mesenchymal transition suggest a role for epigenetic stochasticity as a driving force of cancer, with Darwinian selection of tumour cells at the expense of the host. This increased epigenetic stochasticity appears to be mediated by large-scale changes in DNA methylation and chromatin in domains associated with the nuclear lamina. The implications for diagnosis include the potential to identify stochastically disrupted progenitor cells years before cancer develops, and to target drugs to epigenetic drivers of gene expression instability rather than to mean effects per se.
本篇综述旨在总结人类癌症表观遗传学基础的思维演变，从最早研究癌症中 DNA 甲基化的改变，到现代综合表观基因组学时代。原发肿瘤的表观遗传学研究和发育及上皮间质转化中染色质的实验研究的汇聚数据表明，表观遗传随机性作为癌症的驱动力具有重要作用，肿瘤细胞以牺牲宿主为代价进行达尔文式选择。这种表观遗传随机性的增加似乎是由与核纤层相关的域中 DNA 甲基化和染色质的大规模变化介导的。这一发现对诊断具有重要意义，有可能在癌症发生前数年识别出随机破坏的祖细胞，并将药物靶向于基因表达不稳定的表观遗传驱动因素，而不是针对平均效应本身。
