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Originally published as Genetics Published Articles Ahead of Print on September 2, 2005.
Genetics, Vol. 171, 2123-2131, December 2005, Copyright © 2005
doi:10.1534/genetics.105.040840
Negative Clonal Selection in Tumor Evolution
Robert A. Beckman*,1 and
Lawrence A. Loeb
* Department of Clinical Research and Development, Hematology/Oncology, Centocor, Malvern, Pennsylvania 19355-1307 and Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195-7470
1 Corresponding author: 1045 Hereford Dr., Blue Bell, PA 19422.
E-mail: eniac1{at}snip.net
Development of cancer requires the acquisition of multiple oncogenic mutations and selection of the malignant clone. Cancer evolves within a finite host lifetime and mechanisms of carcinogenesis that accelerate this process may be more likely to contribute to the development of clinical cancers. Mutator mutations are mutations that affect genome stability and accelerate the acquisition of oncogenic mutations. However, mutator mutations will also accelerate the accumulation of mutations that decrease cell proliferation, increase apoptosis, or affect other key fitness parameters. These "reduced-fitness" mutations may mediate "negative clonal selection," i.e., selective elimination of premalignant mutator clones. Target reduced-fitness loci may be "recessive" (both copies must be mutated to reduce fitness) or "dominant" (single-copy mutation reduces fitness). A direct mathematical analysis is applied to negative clonal selection, leading to the conclusion that negative clonal selection against mutator clones is unlikely to be a significant effect under realistic conditions. In addition, the relative importance of dominant and recessive reduced-fitness mutations is quantitatively defined. The relative predominance of mutator mutations in clinical cancers will depend on several variables, including the tolerance of the genome for reduced-fitness mutations, particularly the number and potency of dominant reduced-fitness loci.
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