An appropriate definition of genomic instability is needed before a complete understanding of the interconnecting causes and consequences of genomic instability can be developed, and the contribution of this phenomenon to neoplastic transformation can be appreciated. The observation that most cancer cells contain discernible genetic abnormalities (chromosomal aberrations and/or DNA sequence abnormalities) suggests that all neoplastically transformed cells have sustained genetic damage and might have experienced some form of genomic instability during their development. Normal human cells demonstrate a remarkable degree of genomic integrity, which reflects the combined contributions of high-fidelity DNA replication processes, and the expression of multiple mechanisms that recognize and repair DNA damage. Nonetheless, it is recognized that rare spontaneous mutations can occur in cells that are proficient for both DNA replication and repair. The observation that neoplastic cells contain variable numbers of mutations reflecting specific forms of DNA damage and that tumors develop over widely variable periods of time (from initiation of the transformation process to the outgrowth of a clinically detectable tumor) suggests the possible involvement of different pathogenic mechanisms that might reflect multiple distinct mutagenic pathways to neoplastic transformation. Tumors are highly variable with respect to their growth characteristics; some tumors become clinically evident early in the human life span, whereas others present later in life. This discrepancy could reflect individual differences among tumors and tumor types with respect to the relative rapidity of their development and progression. Consistent with the proposal that tumors form through clonal expansion driven by mutation (1,8,11), tumors displaying early-onset and rapid progression might accumulate a critical level of genetic damage more quickly than tumors with later onset and a more indolent course.
The forms of genetic damage typically displayed by cancer cells (involving chromosomal alterations and/or DNA sequence alterations) are not mutually exclusive. However, the evidence available suggests the involvement of different mutagenic mechanisms in the origins of these genetic abnormalities (65-67). Nonetheless, it is likely that the same groups of target genes might be involved in tumorigenesis driven by the accumulation of either form of genetic damage. Inactivation of the p53 tumor suppressor gene (loss of function) can be accomplished through point mutation at numerous nucleotide sites (26,68) or through deletion of the locus on 17p (69). Likewise, activation of proto-oncogene function can be accomplished by point mutation, as with the H-ras gene (70), or by chromosomal translocation, as with the c-myc gene (71).
Based on these observations, a unifying hypothesis is required to describe the possible mechanisms of genomic instability that can account for the disparate numbers of mutations (specific loci vs widespread mutation) and diverse nature of genetic damage (types of mutation) that characterize various human cancers. We have proposed that at least two broad categories of genomic instability might exist: (1) progressive (persistent) genomic instability and (2) episodic (transient) genomic instability (72). Evidence supporting the existence of these forms of genetic instability has emerged from studies in bacteria (73), and good examples of each of these forms of genomic instability have been identified in subsets of human neoplasms. Progressive or persistent instability defines an ongoing mutagenic process, with new mutations occurring in each cell generation, and is associated with cells that are compromised in their ability to safeguard the integrity of their genome. This form of genomic instability would be transmitted from cell generation to cell generation as a heritable trait (73). For instance, tumor cells from patients with hereditary nonpolypo-sis colorectal cancer (HNPCC) exhibit progressive genomic instability, which is manifest as alterations in microsatellite sequences (74-76). In contrast to progressive instability, episodic or transient instability describes sporadic genetic damage in cells that are otherwise proficient in the various pathways that govern genomic homeostasis. This form of instability is associated with tumors that contain specific mutations and/or chromosomal alterations in the absence of widespread damage to the genome. The transient mutator state might account for a large portion of adaptive mutations occurring in cells (73). For instance, cells exposed to high levels of oxidative or nutritional stress might incur and accumulate adaptive mutations that enable the altered cells to thrive under highly selective conditions. These mutations might occur in cells in the absence of cell proliferation (59,60), but they would facilitate clonal expansion of an altered clone in response to subsequent selection pressures (52). Cells exposed to high levels of reactive oxygen species might accumulate mutations in this manner (77,78). Numerous sporadic tumor types exemplify this form of instability, including sporadic colorectal tumors of the tumor suppressor pathway (79), or the microsatellite mutator pathway (78,80). It can be envisioned that both chromosomal abnormalities and DNA sequence abnormalities could result from the expression of either of these forms of genomic instability during neoplastic transformation.
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