Esteller M
Cancer Epigenetics Laboratory, 3rd Floor, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Br J Cancer. 2006 Jan 30;94(2):179-83. doi: 10.1038/sj.bjc.6602918.
Cancer is nowadays recognised as a genetic and epigenetic disease. Much effort has been devoted in the last 30 years to the elucidation of the 'classical' oncogenes and tumour-suppressor genes involved in malignant cell transformation. However, since the acceptance that major disruption of DNA methylation, histone modification and chromatin compartments are a common hallmark of human cancer, epigenetics has come to the fore in cancer research. One piece is still missing from the story: are the epigenetic genes themselves driving forces on the road to tumorigenesis? We are in the early stages of finding the answer, and the data are beginning to appear: knockout mice defective in DNA methyltransferases, methyl-CpG-binding proteins and histone methyltransferases strongly affect the risk of cancer onset; somatic mutations, homozygous deletions and methylation-associated silencing of histone acetyltransferases, histone methyltransferases and chromatin remodelling factors are being found in human tumours; and the first cancer-prone families arising from germline mutations in epigenetic genes, such as hSNF5/INI1, have been described. Even more importantly, all these 'new' oncogenes and tumour-suppressor genes provide novel molecular targets for designed therapies, and the first DNA-demethylating agents and inhibitors of histone deacetylases are reaching the bedside of patients with haematological malignancies.
如今，癌症被公认为是一种基因和表观遗传疾病。在过去30年里，人们付出了巨大努力来阐明参与恶性细胞转化的“经典”癌基因和肿瘤抑制基因。然而，自从人们认识到DNA甲基化、组蛋白修饰和染色质区室的重大破坏是人类癌症的一个共同特征以来，表观遗传学在癌症研究中占据了突出地位。这个故事中仍缺少一个环节：表观遗传基因本身是否是肿瘤发生过程中的驱动因素？我们正处于寻找答案的早期阶段，相关数据也开始出现：DNA甲基转移酶、甲基-CpG结合蛋白和组蛋白甲基转移酶存在缺陷的基因敲除小鼠会强烈影响癌症发生风险；在人类肿瘤中发现了组蛋白乙酰转移酶、组蛋白甲基转移酶和染色质重塑因子的体细胞突变、纯合缺失以及甲基化相关沉默；并且已经描述了首个由表观遗传基因（如hSNF5/INI1）的种系突变引起的癌症易感家族。更重要的是，所有这些“新的”癌基因和肿瘤抑制基因为设计疗法提供了新靶点，首批DNA去甲基化剂和组蛋白脱乙酰酶抑制剂已应用于血液系统恶性肿瘤患者的临床治疗。
