The mutations that predispose HNPCC individuals to colorectal cancer occur in one of several genes that code for central components of the DNA mismatch repair system. These genes are homologous in structure and function to the MutL and MutS genes in bacteria and yeast (see Figure 5–19). Only one of the two copies of the involved gene is defective, so the repair system is still able to remove the inevitable DNA replication errors that occur in the patient’s cells. However, as discussed previously, these individuals are at risk, because the accidental loss or inactivation of the remaining good gene copy will immediately elevate the spontaneous mutation rate by a hundredfold or more (discussed in Chapter 5). These genetically unstable cells then can presumably speed through the standard processes of mutation and natural selection that allow clones of cells to progress to malignancy.
This particular type of genetic instability produces invisible changes in the chromosomes—most notably changes in individual nucleotides and short expansions and contractions of monoand dinucleotide repeats such as AAAA… or CACACA…. Once the defect in HNPCC patients was recognized, the epigenetic silencing or mutation of mismatch repair genes was found in about 15% of the colorectal cancers occurring in people with no inherited predisposing mutation.
Thus, the genetic instability found in many colorectal cancers can be acquired in at least two ways. The majority of the cancers display a form of chromosomal instability that leads to visibly altered chromosomes, whereas in the others the instability occurs on a much smaller scale and reflects a defect in DNA mismatch repair. Indeed, many carcinomas show either chromosomal instability or defective mismatch repair—but rarely both. These findings clearly demonstrate that genetic instability is not an accidental by-product of malignant behavior but a contributory cause—and that cancer cells can acquire this instability in multiple ways.
The Steps of Tumor Progression Can Often Be Correlated with Specific Mutations
In what order do K-Ras, p53, Apc, and the other identified colorectal cancer-critical genes mutate, and what contribution does each of them make to the asocial behavior of the cancer cell? There is no single answer, because colorectal cancer can arise by more than one route: thus, we know that in some cases, the first mutation can be in a DNA mismatch repair gene; in others, it can be in a gene regulating cell proliferation. Moreover, as previously discussed, a general feature such as genetic instability or a tendency to proliferate abnormally can arise in a variety of ways, through mutations in different genes.
Nevertheless, certain sets of mutations are particularly common in colorectal cancer, and they occur in a characteristic order. Thus, in most cases, mutations inactivating the Apc gene appear to be the first, or at least a very early step, as they are detected at the same high frequency in small benign polyps as in large malignant tumors. Changes that lead to genetic and epigenetic instability are likely also to arise early in tumor progression, since they are needed to drive the later steps.
Activating mutations in the K-Ras gene occur later, as they are rare in small polyps but common in larger ones that show disturbances in cell differentiation and histological pattern.
Inactivating mutations in p53 are thought to come later still, as they are rare in polyps but common in carcinomas (Figure 20–36). We have seen that loss of p53 function allows cancer cells to endure stress and to avoid apoptosis and cell-cycle arrest. Additionally, loss of p53 is related to the heightened activation
Figure 20–35 Chromosome complements (karyotypes) of colon cancers showing different kinds of genetic instability. (A) The karyotype of a typical cancer shows many gross abnormalities in chromosome number and structure. Considerable variation can also exist from cell to cell (not shown).