(B) The karyotype of a tumor that has a stable chromosome complement with few chromosomal anomalies; the genetic abnormalities are mostly invisible, having been created by defects in DNA mismatch repair. All of the chromosomes in this figure were stained as in Figure 4–10, the DNA of each human chromosome being marked with a different combination of fluorescent dyes. (Courtesy Wael Abdel-Rahman and Paul Edwards.) acquisition of increased genetic and epigenetic instability of oncogenes such as Ras. Experiments in mice show that an initial low level of oncogene activation can give rise to a slowly growing tumor even while p53 is functional: genes such as Ras are, after all, part of the normal machinery of growth control, and moderate activation is not stressful for a cell and does not call the p53 protein into play. Progression of a tumor from slow to rapid, malignant growth, however, involves activation of oncogenes beyond normal physiological limits to a higher, stressful level. If the p53 protein is present and functional, this should lead to cell-cycle arrest or death. Only by losing p53 function can the cancer cells with hyperactive oncogenes survive and progress.
The steps we have just described are only part of the picture. It is important to emphasize that each case of colorectal cancer is different, with its own detailed combination of mutations, and that even for the mutations that are commonly shared, the sequence of occurrence may vary. The same is true for cancers in general.
Advances in molecular biology have recently provided the tools to find out precisely which genes are amplified, deleted, mutated, or misregulated by epigenetic mechanisms in the tumor cells of any given patient. As we discuss in the next section, such information promises to become as important for the diagnosis and treatment of cancer as was the breakthrough of being able to identify microorganisms for the treatment of infectious diseases.
The molecular analysis of cancer cells reveals two classes of cancer-critical genes: oncogenes and tumor suppressor genes. A set of these genes becomes altered by a combination of genetic and epigenetic accidents to drive tumor progression. Many cancer-critical genes code for components of the social control pathways that regulate when cells grow, divide, differentiate, or die. In addition, a subclass of tumor suppressors can be categorized as “genome maintenance genes,” because their normal role is to help maintain genome integrity.
The inactivation of the p53 pathway, which occurs in nearly all human cancers, allows genetically damaged cells to escape apoptosis and continue to proliferate. Inactivation of the Rb pathway also occurs in most human cancers, illustrating how fundamental each of these pathways is for protecting us against cancer.
The sequencing of cancer cell genomes reveals that—except for the cancers of childhood—many cancers acquire 10 or so driver mutations over the long course of tumor progression, along with a considerably larger number of passenger mutations of no consequence. The same methods reveal how subclones of cells arise and die out as a tumor ages. Tumors thus contain a heterogeneous mixture of cells, some—the so-called cancer stem cells—being much more dangerous than others.
We can often correlate the steps of tumor progression with mutations that activate specific oncogenes and inactivate specific tumor suppressor genes, with colon cancer providing a good example. But different combinations of mutations and epigenetic changes are found in different types of cancer, and even in different patients with the same type of cancer, reflecting the random way in which these inherited changes arise. Nevertheless, many of the same changes are encountered repeatedly, suggesting that there are a limited number of ways to breach our defenses against cancer.
Figure 20–36 Suggested typical sequence of genetic changes underlying the development of a colorectal carcinoma. This oversimplified diagram provides a general idea of the way mutation and tumor development are related. But many other mutations are generally involved, and different colon cancers can progress through different sequences of mutations (and/or epigenetic changes).
CANCER PREVENTION AND TREATMENT: PRESENT AND FUTURE