Dna Damage And Molecular Alterations In Cancer

Mutations in critical targets leading to neoplastic transformation can result from exogenous insults (carcinogens, radiation) or from endogenous mutagenic factors (45). DNA damage can result from spontaneous alteration of the DNA molecule or from the interaction of numerous chemical and physical agents with the structural DNA molecule. Spontaneous lesions occur during normal cellular processes such as DNA replication, DNA repair, or gene rearrangement or through chemical alterations of the DNA molecule itself as a result of hydrolysis, oxidation, or methylation (12,46). In most cases, DNA lesions create nucleotide mismatches that lead to point mutations. Nucleotide mismatches can result from the formation of apurinic or apyrimidinic sites after depurination or depyrimida-tion reactions, from nucleotide conversions involving deamina-tion reactions, or, in rare instances, from the presence of a tautometric form of an individual nucleotide in replicating DNA. Deamination of nucleotide bases that contain exocyclic amino groups results in the conversion of cytosine to uracil, adenine to hypoxanthine, and guanine to xanthine (47). However, the most common nucleotide deamination reaction involves methylated cytosines. The deamination of 5-methylcytosine, which results in the formation of thymine, accounts for a large percentage of spontaneous mutations in human disease (48).

Interaction of DNA with physical agents, such as ionizing radiation (X-rays), can lead to single-strand or double-strand breaks through sission of phosphodiester bonds on one or both polynucleotide strands of the DNA molecule (47). Ultraviolet (UV) light can produce cyclobutane pyrimidine dimers between adjacent pyrimidine bases on the same DNA strand. Less frequently, UV light produces non-cyclobutane-type pyrimidine dimers or 6-4 photoproducts between adjacent nucleotides in TC, CC, and TT pyrimidine dimers. Other minor forms of DNA damage caused by UV light include strand breaks and crosslinks (47). Nucleotide base modifications can result from exposure of the DNA to various chemical agents, such as N-nitroso compounds and polycyclic aromatic hydrocarbons (47). Among the numerous sites in the chemical structure of the nucleotides subject to modification by alkylating chemicals, the N7 position of guanine and the N3 position of adenine are the most frequently altered. DNA damage can also be caused by chemicals that intercalate the DNA molecule and/or crosslink the DNA strands (47). Bifunctional alkylating agents can cause both intrastrand and interstrand crosslinks in the DNA molecule.


It is widely accepted that cancer cells accumulate numerous genetic abnormalities (consisting of chromosomal alterations and/or nucleotide sequence mutations) during the protracted interval between the initial carcinogenic insult and the outgrowth of a tumor. Although there is evidence that at least a portion of the genetic changes occurring in neoplasia are related to the underlying molecular mechanism of neoplastic transformation (4,5,49), whether the myriad of genetic lesions found in cancer cells are the causes or consequences of neo-plastic transformation continues to be the subject of debate (50). In addition, some investigators have suggested that the intrinsic mutation rate in mammalian cells is insufficient to account for the many genetic changes observed in cancer cells, leading to the suggestion that an early (and possibly essential) step in neoplastic transformation is the development of a condition of hypermutability or genetic instability (51,52). In the past, increased rates of mutation in preneoplastic or neoplastic cells would have been attributed to exposure of these cells to exogenous mutagenic agents. However, more recent analyses of the nature and frequency of mutations occurring in human neoplasms suggests that a significant proportion results from spontaneous mutational mechanisms (53). This observation strengthens the suggestion that cancer cells might exhibit diminished capacities for surveillance and repair of DNA lesions, leading to increased rates of spontaneous mutation and/or increased susceptibility to mutation following exposure to some exogenous carcinogenic agent. An alternative argument suggests that increased rates of mutation are not necessary for the accumulation of large numbers of genetic lesions in cancer cells, but that selection of advantageous mutations is a more important feature of the process of tumorigenesis (52,54).

6.1. SPONTANEOUS MUTATION RATES IN NORMAL CELLS The measured spontaneous mutation rate of mammalian cells depends on the exact experimental conditions employed and the nature of the cells and target sequence examined (55). Somatic mutation rates have been determined for a variety of cultured cell types through examination of the spontaneous mutation frequency at one of several specific loci, such as the hypoxanthine-guanine phosphoribosyltransferase gene, the Na+-K+-ATPase gene, or the adenine phosphoribosyltransferase gene. Using the results from several of these studies (56,57), the spontaneous mutation frequency at the hypoxanthine-guanine phosphoribosyltransferase locus can be estimated to be approx 2.7 x 10-10 to 1 x 10-9 mutations/nucleotide/cell generation in untransformed human cells. This is consistent with calculations made by others for this same locus, where the spontaneous mutation rate was estimated to be 1.4 x 10-10 mutations/ nucleotide/cell generation (58). The latter mutation rate is sufficient to yield approximately three mutations per cell over the life span of an individual, which may be too low to account for the number of mutations thought to be required for carcinogen-esis. This observation led to the hypothesis that an early event in neoplastic transformation might involve an increase in the spontaneous mutation rate in cells that are progressing through this multistep pathway (58). Cells expressing the "mutator phe-notype" accumulate mutations more rapidly than normal cells and would, therefore, be more likely to sustain mutations in critical genes required for enhanced growth and tumorigenesis (59,60).

6.2. MUTATION RATES IN CANCER CELLS In many studies, the measured mutation rate in malignant cells is significantly higher than that of corresponding normal cells. In some cases, the elevated mutation rates were 100-fold higher than in untransformed cells (61,62). Tumor cell lines that are deficient for DNA repair exhibit mutation rates that are 750-fold higher than that displayed by DNA repair-proficient tumor cell lines (63). In addition, the rate of gene amplification in malignant cells is much higher than in normal cells (64). However, other studies find no difference in the spontaneous mutation rate between normal and malignant cells (56,57), or they suggest that selective pressures associated with clonal expansion of altered cells represent a much more important feature of car-cinogenesis than a hypermutational phenotype (54). Thus, some cancer cells might express a "mutator phenotype" and exhibit an enhanced mutation rate compared to normal cells (41), whereas other cancers might exhibit multiple mutations in the absence of any appreciable increase in mutation frequency. These observations suggest the possibility that multiple molecular mechanisms are needed to reconcile the occurrence of multiple mutations in human cancers and the expression of a mutator phenotype with elevated mutational frequency in only a subset of these tumors.

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