Academic journal article Genetics

Negative Clonal Selection in Tumor Evolution

Academic journal article Genetics

Negative Clonal Selection in Tumor Evolution

Article excerpt


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.

DEVELOPMENT of cancer is characterized by the accumulation and selection of multiple genetic changes in key genes altering at least six cancer-associated phenotypes (HANAHAN and WEINBERG 2000). Mutator mutations, defined as mutations that affect genomic stability, may accelerate this process. A mutator mutation in DNA polymerase proofreading activity leads to increased incidence of lymphomas and epithelial tumors in mice (GOLDSBY et al. 2001), and mutations that inactivate a variety of DNA repair enzymes have been shown to result in increased mutation frequency in mice and humans (WOOD et al. 2001). Multiple mutator mutations can cooperate to further destabilize the genome, as has been demonstrated in yeast (MoRRiSON et al. 1993; DATTA et al. 2000).

Tumors evolve within a finite human lifetime. The timescale of appearance of most adult tumors is constant to within less than an order of magnitude, ranging from ^5 years (secondary leukemias after chemotherapy), to 20 years (solid tumors after chemotherapy, occupational carcinogen exposure, or radiation exposure), to a maximum of 50-100 years based on the human life span. Within this fixed time frame, rather than reaching equilibrium, there may be kinetic competition between different mechanisms of carcinogenesis. Mechanisms that accelerate this process may have a greater chance of contributing to carcinogenesis.

The mutator phenotype hypothesis states that mutator mutations contribute to carcinogenesis by accelerating the accumulation of oncogenic mutations (see Figure I)(LoEB et al. 1974, 2003; LOEB 1991, 1998). Mutator mutations and genetic instability are generalized concepts, referring not just to mutations leading to enhanced base substitution, but also to microsatellite instability (MIN) (FISHEL et al. 1993; IONOV et al. 1993), chromosomal instability (CIN) (LENGAUER et al. 1998), and alterations in checkpoint control (SHERR and McCoRMiCK 2002). Both MIN and CIN contribute to the development of colon cancer (LoEB et al. 2003). Tumors appear to contain thousands of mutations, and some of these are in codons and repetitive sequences in which one would not expect mutations to be directly selected (LEVINE 1997; FUTREAL et al. 2004).

When mutator clones acquire increased fitness due to a mutation, they can undergo selection and clonal expansion, further accelerating subseqent steps in carcinogenesis (NOWELL 1976). We term this phenomenon "positive clonal selection" of mutator clones.

One argument against the mutator phenotype hypothesis can be termed "negative clonal selection," defined as selection against mutator clones due to their more rapid acquisition of "reduced-fitness" (RF) mutations. …

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