Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nat Rev Cancer. 2013 Jul;13(7):497-510. doi: 10.1038/nrc3486. Epub 2013 Jun 13.
Although at the genetic level cancer is caused by diverse mutations, epigenetic modifications are characteristic of all cancers, from apparently normal precursor tissue to advanced metastatic disease, and these epigenetic modifications drive tumour cell heterogeneity. We propose a unifying model of cancer in which epigenetic dysregulation allows rapid selection for tumour cell survival at the expense of the host. Mechanisms involve both genetic mutations and epigenetic modifications that disrupt the function of genes that regulate the epigenome itself. Several exciting recent discoveries also point to a genome-scale disruption of the epigenome that involves large blocks of DNA hypomethylation, mutations of epigenetic modifier genes and alterations of heterochromatin in cancer (including large organized chromatin lysine modifications (LOCKs) and lamin-associated domains (LADs)), all of which increase epigenetic and gene expression plasticity. Our model suggests a new approach to cancer diagnosis and therapy that focuses on epigenetic dysregulation and has great potential for risk detection and chemoprevention.
虽然在基因水平上，癌症是由多种突变引起的，但表观遗传修饰是所有癌症的特征，从明显正常的前体组织到晚期转移性疾病，这些表观遗传修饰驱动肿瘤细胞异质性。我们提出了一个癌症的统一模型，其中表观遗传失调允许肿瘤细胞在牺牲宿主的情况下快速选择存活。机制既涉及导致调节表观基因组本身的基因功能紊乱的基因突变，也涉及表观遗传修饰基因突变和异染色质改变。最近的一些令人兴奋的发现也指出了表观基因组的全基因组破坏，涉及到大量 DNA 低甲基化、表观遗传修饰基因的突变和癌症中异染色质的改变（包括大型有组织染色质赖氨酸修饰（LOCKs）和层粘连蛋白相关结构域（LADs）），所有这些都增加了表观遗传和基因表达的可塑性。我们的模型提出了一种新的癌症诊断和治疗方法，侧重于表观遗传失调，具有很大的风险检测和化学预防潜力。
