FAP: A Disease that Virtually Guarentees you get cancer.
Imagine a disorder that virtually guaranteed you'd develop colon cancer not only within your lifetime, but early in it. One such disorder is Familial Adenomatous Polyposis (FAP), also known as Gardner's Syndrome. In the review article, Familial adenomatous polyposis, by Elizabeth Half, Dani Bercovich, and Paul Rozen, the specifics of this remarkable and deadly disorder are laid out.
The statistics associated with FAP are fairly shocking. While it only has an incidence at birth rate of 1/8300 and constitutes less than 1% of cases of adenocarcinoma of the colon, the disorder virtually guarantees the sufferer will develop colon cancer int heir lifetime. In people positive for FAP, colon polyps, growths in the mucous lining of an organ, start forming as soon as early childhood and only increase in size and quantity from that point on. While polyps generally aren't malignant, they can become malignant over time. By the age of 15, around half of FAP patients have developed polyps and by age 35, 95% of those with FAP will have done so. The true horror of FAP, though, isn't the number of individuals that develop polyps, but the quantity in which they do. By the age of 20, a large portion of patients will already have developed anywhere from tens to thousands of benign polyps, known as adenomas, every one of which has the potential to become a carcinoma. Figure 1 (below) illustrates just how prevalent the adenomas become within the FAP patient.
Figure 1. Early adenomas in the colon of a patient with Familial Adenomatous Polyposis (FAP).
This is a picture taken during a colonoscopy of a patient suffering from FAP that shows adenomas early in development. Each roundish discoloration is likely an ademona that is just starting to form. Keep in mind that the half dozen or so possible adenomas present in this picture all reside within a patch of flesh smaller than a silver dollar. You can compare this with Figure 2 (below) which demonstrates established adenomas in an FAP patient.
Figure 2. Established adenomas in the colon of a patient with Familial Adenomatous Polyposis (FAP).
As can clearly be seen, the the formation of adenomas can be overwhelming. A person with an adenoma concentration this dense likely has a total polyp count well into the thousands, each one representing a possible carcinoma. Under normal circumstances, a person would usually have anywhere between 0 and 10 polyps form in their lifetime with the majority of them forming past the age of 50. However, the concentration of polyps seen in Figure 2 can be seen in FAP patients as young as 20.
So the question remains; what is happening in patients with Familial Adenomatous Polyposis?
The answer lies within the adenomatous polyposis coli (APC) gene. APC is a tumor suppressor gene, like we learned about in class. Functional APC interacts with myriad intracellular proteins and acts on pathways that play a variety of roles within the cell. However, its role as a tumor suppressor is linked primarily to its part in the Wnt signaling pathway (Figure 3, circled in red). In this pathway, APC regulates the degradation of β-catenin. Active APC causes β-catenin to be degraded, which in tern destabilizes a protein complex to which it belongs. When stable this protein targets several genes for expression, most notably c-myc. The expression of c-myc in turn leads to the expression of polamine ornithine decarboxylase (ODC), a proto-oncogene. Though the connection is indirect, APC regulates a number of genes involvede in cell proliferation. In patients with FAP generally have a deletion within the APC gene that causes a stop codon to appear prematurely. As a result, the APC protein is truncated and loses functionality. The nonfunctional APC proteins fail to signal the ubiquitin-mediated destruction of β-catenin, which cause the protein complex to which it belongs to remain stable and promote the expression of c-myc and, by extension, the proto-oncogene, ODC. Over expression of ODC leads to unsignalled cell proliferation, leading to the formation of adenomas and possibly carcinomas.
Figure 3. Some signalling pathways within the human cell. The Wnt signalling pathway has been circled in red on the upper right. (Photo source: http://en.wikipedia.org/wiki/File:Signal_transduction_v1.png)
An important fact to keep in mind is that FAP is an autosomal dominant disease. This means that even with a functional copy of the APC gene, β-catenin is still not properly regulated. I assume that without two functional copies of the APC gene, the concentration of functional APC is not high enough to trigger normal levels of ubiquitin-mediated β-catenin destruction. Even if there is some regulation, it is not enough to prevent over expression of the ODC proto-oncogene. I attempted to investigate further by comparing the phenotypes of heterozygous FAP patients with homozygous FAP patients. However, despite my efforts I was unable to locate any papers detailing anything about homozygous FAP patients. In hindsight, this makes sense as the APC protein is involved in embryogenesis. Without a functional copy of the APC gene, embryogenesis could not function normally and no viable offspring with that genotype could be produced.
The main question that irks me concerning Familial Adenomatous Polyposis is; why does it lead to primarily adenocarcinoma of the colon and not the many other types of cancer? The APC tumor suppressor gene should be playing a role in all proliferating cells, thus I would expect to see FAP promoting every type of cancer imaginable. Its known to lead to adenocarcinoma throughout the gastrointestinal tract (though most notably in the colon), but the carcinogenic effects should be more widespread. The best explanation I can come up with is that adenomas occur within the mucous lining of the gastrointestinal tract which, as an epithelial layer, would experience more wear and tear and, by extension, cell turnover. The accelerated proliferation of these cells would provide a greater number of opportunities for β-catenin to become under-regulated within a cell, leading to an overall number of adenomas.
Half, Elizabeth; Bercovich, Dani; Rozen, Paul. (2009). Familial adenomatous polyposis. Orphanet Journal of Rare Diseases 2009, 4:22.