A Mutator Phenotype in Cancer

Perspectives in Cancer Research

A Mutator Phenotype in Cancer¹

Lawrence A. Loeb²

Departments of Pathology and Biochemistry, The Joseph Gottstein Memorial Cancer Research Laboratory, University of Washington, Seattle, Washington 98195-7705

ABSTRACT

We have proposed that an early step in tumor progression isthe expression of a mutator phenotype resulting from mutationsin genes that normally function in the maintenance of geneticstability. There is new and strong experimental evidence thatsupports the concept of a mutator phenotype in cancer. As technologiesfor chromosomal visualization and DNA advance, there are increasingdata 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 cellscontain thousands of mutations. Third, I will explore potentialtarget genes that are required for maintenance of genetic stabilityin normal cells and ask if they are mutated in cancer cells.Fourth, I will address the timing of a mutator phenotype; isit an early event during tumor progression? Do tumors alreadycontain cells that harbor mutations rendering them resistantto most chemotherapeutic agents? Lastly, I will speculate onthe theoretical and practical implication of a mutator phenotypein cancer and consider the possibility of cancer preventionby delay, i.e., a reduction in mutation rates early during carcinogenesismight slow the progression of tumors.

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P. A. Egner, J.-B. Wang, Y.-R. Zhu, B.-C. Zhang, Y. Wu, Q.-N. Zhang, G.-S. Qian, S.-Y. Kuang, S. J. Gange, L. P. Jacobson, et al.
Chlorophyllin intervention reduces aflatoxin-DNA adducts in individuals at high risk for liver cancer
PNAS, December 4, 2001; 98(25): 14601 - 14606.
[Abstract] [Full Text] [PDF]

T.-L. Wang, C. Rago, N. Silliman, J. Ptak, S. Markowitz, J. K. V. Willson, G. Parmigiani, K. W. Kinzler, B. Vogelstein, and V. E. Velculescu
Prevalence of somatic alterations in the colorectal cancer cell genome
PNAS, March 5, 2002; 99(5): 3076 - 3080.
[Abstract] [Full Text] [PDF]