期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 48, 页码 18238-18242出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0607057103
关键词
genetic instability; random mutation frequency; umor heterogeneity; nucleotide instability (NIN); carcinogenesis
资金
- NCI NIH HHS [R01 CA102029, CA78885, R01 CA078885, CA102029] Funding Source: Medline
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.
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