Figure 20–25 The mutation landscape in colorectal cancer. In this two-dimensional representation of the human genome, the green surface depicts the 22 human autosomes plus the X sex chromosome as being laid out side-by-side in numerical order from left to right, with the DNA sequence of each chromosome running from back to front. The mountains represent the locations of genes mutated with high frequency in different, independent tumors. As indicated, these are suspected driver mutations in the adenomatous polyposis coli (APC), K-Ras, p53, phosphoinositide 3-kinase (PIK3CA), and ubiquitin ligase (FBXW7) proteins. (Adapted from L.D. Wood et al., Science 318:1108–1113, 2007.)
By compiling the data for different types of cancer, each with its own range of identified driver mutations, we can develop a comprehensive catalog of genes that are strongly suspected to be cancer-critical. Current estimates put the total number of such genes at about 300, about 1% of the genes in the human genome. These cancer-critical genes are amazingly diverse. Their products include secreted signal proteins, transmembrane receptors, GTP-binding proteins, protein kinases, transcription regulators, chromatin modifiers, DNA repair enzymes, cell–cell adhesion molecules, cell-cycle controllers, apoptosis regulators, scaffold proteins, metabolic enzymes, components of the RNA splicing machinery, and more besides. All these are susceptible to mutations that can contribute, in one way or another, in one tissue or another, to the evolution of cells with the cancerous properties that we listed earlier on page 1103.
Clearly, the molecular changes that cause cancer are complex. As we now explain, however, the complexity is not quite as daunting as it may initially seem.
Disruptions in a handful of Key Pathways Are Common to Many Cancers
Some genes, like Rb and Ras, are mutated in many cases of cancer and in cancers of many different types. The involvement of genes such as Rb and Ras in cancer is no surprise, now that we understand their normal functions: they control fundamental processes of cell division and growth. But even these common culprits feature in considerably less than half of individual cases. What is happening to the control of these processes in the many cases of cancer where, for example, Rb is intact or Ras is not mutated? What part do mutations in the hundreds of other cancer-critical genes play in the development of the disease? With our increasing knowledge of the normal functions of the genes in the human genome, it is becoming easier to see patterns in the cataloged driver mutations and to give some simplifying answers to these questions.
Glioblastoma—the commonest type of human brain tumor—provides a good example. Analysis of the genomes of tumor cells from 91 patients identified a total of at least 79 genes that were mutated in more than one individual. The normal functions of most of these genes were known or could be guessed, allowing them to be assigned to specific biochemical or regulatory pathways. Three functional groupings stood out, accounting for a total of 21 of the recurrently mutated genes. One of these groupings consisted of genes in the Rb pathway (that is, Rb itself, along with genes that directly regulate Rb); this pathway governs initiation of the cell-division cycle. Another consisted of genes in the same regulatory subnetwork as Ras—a more loosely defined system of genes referred to as the RTK/Ras/PI3K pathway, after three of its core components; this pathway serves to transmit signals for cell growth and cell division from the cell exterior into the heart of the cell. The third grouping consisted of genes in a pathway regulating responses to stress and DNA damage—the p53 pathway. We shall have more to say about each of these pathways below.