Plass Christoph, Soloway Paul D
Division of Human Cancer Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Eur J Hum Genet. 2002 Jan;10(1):6-16. doi: 10.1038/sj.ejhg.5200768.
It is well known that a variety of genetic changes influence the development and progression of cancer. These changes may result from inherited or spontaneous mutations that are not corrected by repair mechanisms prior to DNA replication. It is increasingly clear that so called epigenetic effects that do not affect the primary sequence of the genome also play an important role in tumorigenesis. This was supported initially by observations that cancer genomes undergo changes in their methylation state and that control of parental allele-specific methylation and expression of imprinted loci is lost in several cancers. Many loci acquiring aberrant methylation in cancers have since been identified and shown to be silenced by DNA methylation. In many cases, this mechanism of silencing inactivates tumour suppressors as effectively as frank mutation and is one of the cancer-predisposing hits described in Knudson's two hit hypothesis. In contrast to mutations which are essentially irreversible, methylation changes are reversible, raising the possibility of developing therapeutics based on restoring the normal methylation state to cancer-associated genes. Development of such therapeutics will require identifying loci undergoing methylation changes in cancer, understanding how their methylation influences tumorigenesis and identifying the mechanisms regulating the methylation state of the genome. The purpose of this review is to summarise what is known about these issues.
众所周知，多种基因变化会影响癌症的发生和发展。这些变化可能源于遗传或自发突变，在DNA复制之前未被修复机制纠正。越来越明显的是，所谓的表观遗传效应（不影响基因组的一级序列）在肿瘤发生中也起着重要作用。最初的观察结果支持了这一点，即癌症基因组的甲基化状态会发生变化，并且在几种癌症中，亲本等位基因特异性甲基化的控制和印记位点的表达会丧失。此后，许多在癌症中获得异常甲基化的位点已被鉴定出来，并显示因DNA甲基化而沉默。在许多情况下，这种沉默机制与明显的突变一样有效地使肿瘤抑制基因失活，并且是克努森的双击假说中描述的癌症易感性打击之一。与基本上不可逆的突变不同，甲基化变化是可逆的，这增加了基于将癌症相关基因的甲基化状态恢复正常来开发治疗方法的可能性。开发此类治疗方法需要识别癌症中发生甲基化变化的位点，了解它们的甲基化如何影响肿瘤发生，并识别调节基因组甲基化状态的机制。本综述的目的是总结关于这些问题的已知信息。
