Human cancers express a mutator phenotype
Human cancers express a mutator phenotype
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DOI：
10.1073/pnas.0607057103
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发表时间：
2006-11-28
影响因子：
11.1
通讯作者：
Loeb, Lawrence A.
中科院分区：
文献类型：
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作者：
Bielas, Jason H.;Loeb, Keith R.;Loeb, Lawrence A.
癌细胞含有许多克隆突变，即，突变存在于肿瘤的大多数或所有恶性细胞中，并且可能因为它们赋予增殖优势而被选择。一个重要的问题是癌细胞是否也含有大量的随机突变，即，随机分布的突变，仅发生在肿瘤的一个或几个细胞中。这种随机突变可能会导致癌症的形态和功能异质性，并包括对治疗产生耐药性的突变。我们假设恶性细胞表现出一种增变基因表型，导致整个基因组产生随机突变。我们最近开发了一种检测方法，以前所未有的灵敏度定量人体组织中的随机突变。在这里，我们报告的测量随机单核苷酸取代在正常和肿瘤人体组织。在正常组织中，自发随机突变的频率非常低，每对碱基不到1 × 10（-8）。相比之下，来自相同个体的肿瘤显示出每个碱基对210 x 10-8的平均频率，至少提高了两个数量级。我们的数据在单核苷酸水平上记录了肿瘤的异质性，表明加速突变在肿瘤进展后期普遍存在，并表明肿瘤中随机突变频率的升高可能作为一种新的预后指标。
Cancer cells contain numerous clonal mutations, i.e., mutations that are present in most or all malignant cells of a tumor and have presumably been selected because they confer a proliferative advantage. An important question is whether cancer cells also contain a large number of random mutations, i.e., randomly distributed unselected mutations that occur in only one or a few cells of a tumor. Such random mutations could contribute to the morphologic and functional heterogeneity of cancers and include mutations that confer resistance to therapy. We have postulated that malignant cells exhibit a mutator phenotype resulting in the generation of random mutations throughout the genome. We have recently developed an assay to quantify random mutations in human tissue with unprecedented sensitivity. Here, we report measurements of random sing le-nucleotide substitutions in normal and neoplastic human tissues. In normal tissues, the frequency of spontaneous random mutations is exceedingly low, less than 1 X 10(-8) per base pair. In contrast, tumors from the same individuals exhibited an average frequency of 210 x 10-8 per base pair, an elevation of at least two orders of magnitude. Our data document tumor heterogeneity at the single-nucleotide level, indicate that accelerated mutagenesis prevails late into tumor progression, and suggest that elevation of random mutation frequency in tumors might serve as a novel prognostic indicator.