Multiple Mutations In Cancer

In most cases, it takes years for a full-blown invasive, metastatic cancer to develop from a small clone of initiated cells. This process might take 20 years or more, during which time an initiated clone of cells undergoes clonal expansion via multiple cell doublings. As these clones expand, various cells in the population accumulate multiple genetic alterations, some of which facilitate dysregulated cell proliferation and some of which lead to cell death. These genetic alterations can include point mutations, chromosomal translocations, gene deletions, gene amplifications, loss of genetic heterozygosity (LOH), and loss of genetic imprinting (LOI). These will be discussed in detail in Chapter 5. This accumulation of genetic defects that occurs during clonal expansion of transformed cells is due to ''genetic instability." The cause of this genetic instability is not clearly understood, but it includes defects in cell replication checkpoint controls and decreased ability to repair DNA damage.

There is evidence for the accumulation of thousands of mutations in cancer cells derived from human tumors. For example, examination of the colon tumor-derived DNA from patients with hereditary non-polyposis colon cancer (HNPCC) reveals that as many as 100,000 repetitive DNA sequences are altered from the mismatch DNA repair defects that these patients' cells harbor (reviewed in Reference 122). Mismatch repair defects have also been noted in ''sporadic'' (not known to be hereditary) cancers.

As noted earlier, one hypothesis explaining the genetic instability of transformed cells is the mutator phenotype hypothesis, championed by Loeb and colleagues.122 This hypothesis states that an ''initial mutator [gene] mutation generates further mutations including mutations in additional genetic stability genes, resulting in a cascade of mutations throughout the genome." The molecular defect that could provide this phenotype could be a mutation in DNA polymerases that leads to error-prone DNA replication. The mutator phenotype would have to be generated early in tumorigenesis for this hypothesis to be valid. There are a number of arguments against this idea, such as observations that there is not necessarily an increased mutation rate in cancer cells over that of normal cells123 and that a similar ''evolution'' of genetically altered cancer cells could arise by clonal selection followed by clonal expansion of cells with a genetic alteration that provides a prolif-erative advantage.124

10 Ways To Fight Off Cancer

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