Genetic alterations and DNA repair in human carcinogenesis
Genetic alterations and DNA repair in human carcinogenesis
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DOI：
10.1016/j.semcancer.2004.06.007
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发表时间：
2004-12-01
影响因子：
14.5
通讯作者：
Kopras, E
中科院分区：
文献类型：
--
作者：
Dixon, K;Kopras, E
大量实验和流行病学数据支持遗传改变与癌症之间的因果关系。肿瘤抑制基因的突变失活和癌基因的激活与多种癌症的发生有关。对于化学暴露诱发的癌症来说，突变和致癌之间的联系尤其明显，在某些情况下，化学暴露会导致特征性的突变模式。这些“基因毒性”的直接致癌物与 DNA 形成共价加合物，在 DNA 复制过程中引起突变。 DNA 修复缺陷与癌症风险增加相关的观察也支持了突变和致癌之间的联系。通常，DNA 修复机制通过在 DNA 损伤导致可遗传突变之前纠正 DNA 损伤来抑制突变。据推测，突变在癌变的起始阶段和进展阶段均发挥作用，并且致癌过程中的一个重要步骤是突变状态的发展，在该状态中，抑制突变的正常细胞过程受到损害。鉴于突变与癌症之间的联系，人们尝试使用癌细胞的突变谱作为致病因子的指标。虽然这在某些情况下可能是一种有效的方法，但由于内源过程在促进诱变中的作用而变得复杂。此外，许多重要的致癌物质可能通过抑制DNA修复功能或刺激不适当的细胞增殖来间接增强诱变。表观遗传现象也可能抑制基因表达，但不会引起 DNA 序列的明显变化。 (C) 2004 Elsevier Ltd. 保留所有权利。
A causal association between genetic alterations and cancer is supported by extensive experimental and epidemiological data. Mutational inactivation of tumor suppressor genes and activation of oncogenes are associated with the development of a wide range of cancers. The link between mutagenesis and carcinogenesis is particularly evident for cancers induced by chemical exposures, which, in some cases, lead to characteristic patterns of mutations. These "genotoxic," direct-acting carcinogens form covalent adducts with DNA, which cause mutations during DNA replication. The link between mutagenesis and carcinogenesis is also supported by the observation that DNA repair defects are associated with an increased cancer risk. Normally, DNA repair mechanisms serve to suppress mutagenesis by correcting DNA damage before it can lead to heritable mutations. It has been postulated that mutagenesis plays a role in both the initiation phase and the progression phase of carcinogenesis, and that an essential step in the carcinogenic process is the development of a mutator state in which the normal cellular processes that suppress mutagenesis become compromised. Given the link between mutations and cancer, attempts have been made to use the mutational profile of cancer cells as an indicator of the causative agent. While this may be a valid approach in some cases, it is complicated by the role of endogenous processes in promoting mutagenesis. In addition, many important carcinogenic agents may enhance mutagenesis indirectly through suppression of DNA repair functions or stimulation of inappropriate cell proliferation. Epigenetic phenomena may also suppress gene expression without causing overt changes in DNA sequence. (C) 2004 Elsevier Ltd. All rights reserved.