Loeb L A
Joseph Gottstein Memorial Cancer Research Laboratory, Department of Pathology, University of Washington, Seattle 98195-7705, USA.
Adv Cancer Res. 1998;72:25-56. doi: 10.1016/s0065-230x(08)60699-5.
This review analyzes the concept and evidence in support of a mutator phenotype in human cancer. The large number of mutations reported in tumor cells cannot be accounted for by the low mutation rates observed in normal somatic cells; rather, it must be a manifestation of a mutator phenotype present early during the tumorigenic process. The interaction between increased mutagenesis and clonal selection provides a mechanism for the selection of cells with increased proliferative advantage. The concept of a mutator phenotype in cancer has gained considerable support from the findings of enormous numbers of somatic mutations in repetitive sequences in human tumors. Moreover, cell lines exhibiting microsatellite instability demonstrate an increased mutation frequency in expressed genes. A knowledge of mechanisms that generate multiple mutations in cancer cells has important implications for prevention. For many tumors, a delay in the rate of accumulation of mutations by a factor of two could drastically reduce the death rates from these tumors.
本综述分析了支持人类癌症中突变体表型的概念及证据。肿瘤细胞中报告的大量突变无法用正常体细胞中观察到的低突变率来解释；相反，它必定是肿瘤发生过程早期存在的突变体表型的一种表现。诱变增加与克隆选择之间的相互作用为选择具有增殖优势增加的细胞提供了一种机制。癌症中突变体表型的概念已从人类肿瘤中重复序列大量体细胞突变的发现中获得了相当多的支持。此外，表现出微卫星不稳定性的细胞系在表达基因中显示出增加的突变频率。了解癌细胞中产生多个突变的机制对预防具有重要意义。对于许多肿瘤来说，将突变积累速率延迟两倍可能会大幅降低这些肿瘤的死亡率。
