Loeb L A
Departments of Pathology and Biochemistry, The Joseph Gottstein Memorial Cancer Research Laboratory, University of Washington, Seattle, WA 98195-7705, USA.
Cancer Res. 2001 Apr 15;61(8):3230-9.
We have proposed that an early step in tumor progression is the expression of a mutator phenotype resulting from mutations in genes that normally function in the maintenance of genetic stability. There is new and strong experimental evidence that supports the concept of a mutator phenotype in cancer. As technologies for chromosomal visualization and DNA advance, there are increasing data that human cancer cells contain large numbers of mutations. First, I will review the concept of a mutator phenotype. Second, I will present the recent evidence that individual cancer cells contain thousands of mutations. Third, I will explore potential target genes that are required for maintenance of genetic stability in normal cells and ask if they are mutated in cancer cells. Fourth, I will address the timing of a mutator phenotype; is it an early event during tumor progression? Do tumors already contain cells that harbor mutations rendering them resistant to most chemotherapeutic agents? Lastly, I will speculate on the theoretical and practical implication of a mutator phenotype in cancer and consider the possibility of cancer prevention by delay, i.e., a reduction in mutation rates early during carcinogenesis might slow the progression of tumors.
我们已经提出，肿瘤进展的早期步骤是由于通常在维持遗传稳定性中起作用的基因突变而导致的突变体表型的表达。有新的强有力的实验证据支持癌症中突变体表型的概念。随着染色体可视化和DNA技术的进步，越来越多的数据表明人类癌细胞含有大量突变。首先，我将回顾突变体表型的概念。其次，我将展示最近的证据，即单个癌细胞含有数千个突变。第三，我将探索正常细胞维持遗传稳定性所需的潜在靶基因，并询问它们在癌细胞中是否发生了突变。第四，我将探讨突变体表型出现的时间；它是肿瘤进展过程中的早期事件吗？肿瘤是否已经含有携带突变的细胞，使其对大多数化疗药物具有抗性？最后，我将推测突变体表型在癌症中的理论和实际意义，并考虑通过延迟预防癌症的可能性，即致癌早期突变率的降低可能会减缓肿瘤的进展。
