Figure 20–34 Colon of familial adenomatous polyposis coli patient compared with normal colon. (A) The normal colon wall is a gently undulating but smooth surface. (B) The polyposis colon is completely covered by hundreds of projecting polyps, each resembling a tiny cauliflower when viewed with the naked eye. (Courtesy of Andrew Wyllie and Mark Arends.) adenomatous polyposis coli (FAP). In this syndrome, hundreds or thousands of polyps develop along the length of the colon (Figure 20–34). These polyps start to appear in early adult life, and if they are not removed, one or more will almost always progress to become malignant; the average time from the first detection of polyps to the diagnosis of cancer is 12 years. The disease can be traced to a deletion or inactivation of the tumor suppressor gene Apc, named after the syndrome. Individuals with FAP have inactivating mutations or deletions of one copy of the Apc gene in all their cells and show loss of heterozygosity in tumors, even in the benign polyps. Most patients with colorectal cancer do not have the hereditary condition. Nevertheless, in more than 80% of the cases, their cancer cells (but not their normal cells) have inactivated both copies of the Apc gene through mutations acquired during the patient’s lifetime. Thus, by a route similar to that which we discussed for retinoblastoma, mutation of the Apc gene was identified as one of the central ingredients of colorectal cancer.
The Apc protein, as we now know, is an inhibitory component of the Wnt signaling pathway (discussed in Chapter 15). It binds to the β-catenin protein, another component of the Wnt pathway, and helps to induce the protein’s degradation. By inhibiting β-catenin in this way, Apc prevents the β-catenin from migrating to the nucleus, where it would act as a transcriptional regulator to drive cell proliferation and maintain the stem-cell state (see Figure 15–60). Loss of Apc results in an excess of free β-catenin and thus leads to an uncontrolled expansion of the stem-cell population. This causes massive increase in the number and size of the intestinal crypts (see Figure 22–4).
When the β-catenin gene was sequenced in a collection of colorectal tumors, it was discovered that, many of the tumors that did not have Apc mutations had activating mutations in β-catenin instead. Thus, it is excessive activity in the Wnt signaling pathway that is critical for the initiation of this cancer, rather than any single oncogene or tumor suppressor gene that the pathway contains.
This being so, why is the Apc gene in particular so often the most common culprit in colorectal cancer? The Apc protein is large and it interacts not only with β-catenin but also with various other cell components, including microtubules. Loss of Apc appears to increase the frequency of mitotic spindle defects, leading to chromosome abnormalities when cells divide. This additional, independent cancer-promoting effect could explain why Apc mutations feature so prominently in the causation of colorectal cancer.
In addition to the hereditary disease (FAP) associated with Apc mutations, there is a second, more common kind of hereditary predisposition to colon carcinoma in which the course of events differs from the one we have described for FAP. In this more common condition, called hereditary nonpolyposis colorectal cancer (HNPCC), the probability of colon cancer is increased without any increase in the number of colorectal polyps (adenomas). Moreover, the cancer cells are unusual, in that they have a normal (or almost normal) karyotype. The majority of colorectal tumors in non-HNPCC patients, in contrast, have gross chromosomal abnormalities, with multiple translocations, deletions, and other aberrations, as well as having many more chromosomes than normal (Figure 20–35).