In ovarian cancers, for example, chromosome breaks, translocations, and deletions are very common, and these aberrations correlate with a high frequency of mutations and epigenetic silencing in the genes needed for repair of DNA double-strand breaks by homologous recombination, especially Brca1 and Brca2 (see pp. 281–282). In a subset of colorectal cancers with DNA mismatch repair defects, on the other hand, one instead finds many point mutations scattered throughout the genome (see pp. 250–251). In both kinds of cancer, the genome is commonly destabilized, but different types of mutations can bring this about.
Cancers of Specialized Tissues Use Many Different Routes to Target the Common Core Pathways of Cancer
Mutations in core components of the machinery that regulates cell growth, division, and survival, such as Rb, Ras, PTEN, or p53, are not the only way to pervert the control of these processes. Specialized tissues depend on a variety of pathways, as discussed in Chapter 15, to relay environmental signals to the core control machinery, and each pathway lays the cells open to subversion in a different set of ways. Thus, in different cancers, we can find examples of driver mutations in practically all the major signaling pathways through which cells communicate during development and tissue maintenance (discussed in Chapters 21 and 22).
In glioblastoma, for example, most patients have mutations in one or other of a set of cell-surface receptor tyrosine kinases, especially the EGF receptor mentioned earlier (linking into the Ras/PI3K pathway), suggesting that the cells from which the cancer originates are normally controlled by this route. The cells of the prostate gland, on the other hand, respond to the androgen hormone testosterone, and in prostate cancer, components of the androgen receptor signaling pathway (a variety of nuclear hormone receptor signaling; see Chapter 15) are often mutated. In the normal gut lining, Wnt signaling is critical, and Wnt pathway mutations are present in most colorectal cancers. Pancreatic cancers generally have mutations in the transforming growth factor-β (TGFβ) signaling pathway. Activating mutations in the Notch pathway are present in more than 50% of T cell acute lymphocytic leukemias, and so on.
Cells are generally regulated by several different types of external signals that must act in combination, representing a “fail-safe” control mechanism that protects the organism as a whole from cancer. These signals are different in different tissues. As expected, therefore, the corresponding cancers often have mutations in several signaling pathways concurrently. This is true of the examples we have just listed, which commonly have mutations in other signaling pathways in addition to the ones that we have singled out.
Studies Using Mice help to Define the Functions of Cancer-Critical Genes
The ultimate test of a gene’s role in cancer has to come from investigations in the intact, mature organism. The most favored organism for such studies, apart from humans themselves, is the mouse. To explore the function of a candidate oncogene or tumor suppressor gene, one can make a transgenic mouse that overexpresses it or a knockout mouse that lacks it. Using the techniques described in Chapter 8, one can engineer mice in which the misexpression or deletion of the gene is restricted to a specific set of cells, or in which expression of the gene can be switched on at will at a chosen point in time, or both, to see whether and how tumors develop. Moreover, to follow the growth of tumors from day to day in the living organism, the cells of interest can be genetically marked and made visible by expression of a fluorescent or luminescent reporter (Figure 20–28). In these ways, one can begin to clarify the part that each cancer-critical gene plays in cancer initiation or progression.