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.
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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.
Sources:
Half, Elizabeth; Bercovich, Dani; Rozen, Paul. (2009). Familial adenomatous polyposis. Orphanet Journal of Rare Diseases 2009, 4:22.
