Familial adenomatous polyposis

Video summary

Familial adenomatous polyposis (FAP) is a rare, autosomal dominant condition characterized by the development of many polyps in the colon and rectum. These polyps can become cancerous over time, leading to a high risk of developing colorectal cancer. Surgery is often recommended to remove the polyps and prevent cancer from developing.

FAP is caused by mutations in the adenomatous polyposis coli (APC) gene. This gene normally helps to suppress tumor growth in the colon. When it is mutated, this function is lost, resulting in an increased risk of developing tumors. FAP can be diagnosed through genetic testing.

Watch video only
With familial adenominous polyposis or simply FAP. Familial means the condition runs in families.
Polyposis indicates the presence of many polyps, and adenominous describes the specific type of polyps that develop. So FAP is an autosomal dominant condition that causes 100s to thousands of adenominous polyps to form in the colon and rectum.
Now the colon and rectum have an inner lining called the mucosa, which consists of a single layer of column-shaped epithelial cells dotted with tiny pits called crypts.
These cells continuously renew themselves. Older cells at the surface die off, while new ones form at the base of the crypts and gradually move upward to take their place.
This renewal process is carefully regulated by various genes, including the Adenominous polyposis coli or APC. The APC gene is located on the long arm of chromosome 5, at the specific locus 5Q2122, and encodes the APC protein.
The APC protein is a part of the WNT signaling pathway, which regulates cell growth and division. This signaling pathway begins with WNT proteins, which are messengers that bind special frizzled receptors on the cell surface.
When activated, these receptors trigger a series of intracellular events that involve the APC protein and another protein called beta-catenin.
Now APC works as a tumor suppressor, putting the brakes on cell growth and division, while beta-catenin is a proto-oncoprotein that constantly tries to reach the nucleus and stimulate growth.
These two work closely together because APC keeps beta-catenin in check. Normally when there are no WNT molecules to activate the frizzled receptors, the APC protein forms a destruction complex that breaks down beta-catenin.
As a result, the signal never reaches the nucleus, keeping the cell stable and preventing uncontrollable growth. However, when WNT molecules bind the receptors, the cell blocks the formation of the APC destruction complex.
This enables beta cattenin to move into the nucleus and activate genes responsible for growth in the colon. This careful balance ensures that new cells replace old ones at just the right rate, not too fast, not too slow.
But in FAP that balance starts to shift. In this case, a person inherits one mutated copy of the APC gene that produces a faulty APC protein.
This first mutation, known as the first hit, doesn't cause immediate trouble because the second copy of the gene still works and produces enough APC protein to keep the WNT pathway in check.
However, even though cell growth remains steady for now, this mutation sets the stage and puts every cell on a risky path.
Sooner or later, the second hit will happen, and the other copy of the APC gene will also mutate, and because inheriting just one faulty copy increases the risk so much, FAP is considered an autosomal dominant condition.
On the flip side, in about 20% of cases, the mutation occurs de novo, meaning it's not passed down from the parent, but arises spontaneously in a new generation.
Whether the first mutation is inherited or occurs de novo, once the cell takes the second hit, it can't produce any functional APC proteins.
It's like losing both the foot brake and the hand brake on a car. Nothing is left to slow things down.
Without breaks, the WNT pathway runs wild because nothing stops beta-catenin from pushing the cells to grow and divide. These uncontrolled cells pile up, forming small growths called adenominous polyps, which come in different shapes.
Some lie flat against the lining of the colon, while others are pedunculated, meaning they grow on stalks like tiny mushrooms.
The last type includes sessile polyps, which have a broad base that makes them stick out. By adulthood, a person with FAP often develops 100s or even thousands of these polyps, mostly in the descending colon and rectum.
Beyond the colon, polyps can develop in other parts of the digestive tract, including the stomach and small intestine. Next, under a microscope, these polyps reveal themselves as adenomas, which come in three types.
First, tubular adenomas, the most common type, contain many hollow tube-like structures. Villus adenomas have tiny tree-like branches.
These are more dangerous because they carry the highest risk of becoming cancerous, and you can remember them as the villain adenomas.
Finally, tubulo villous adenomas combine features of both and carry a moderate risk. Although these polyps start out as benign, they often become malignant over time.
This occurs when cells accumulate additional mutations in other important genes that control growth, like KRAS and P53. It's like a numbers game.
If left untreated, it's almost certain that at least one of the thousands of polyps will acquire an additional mutation and become malignant, usually by age 30.
But not everyone with FAP faces the same level of risk. This aggressive form of FAP is also known as classic FAP, but some people develop a milder version known as attenuated FAP, which progresses more slowly and carries a lower risk of cancer.
And that's not all. Beyond varying levels of risk, FAP doesn't have to follow the same story for everyone.
Sometimes a specific type of mutation in the APC gene adds a new chapter to the book. One of these chapters is Gardner syndrome.
In this version, interstitial polyps are still present, but other features begin to appear outside the gastrointestinal system.
Specifically, a body might develop benign bone tumors of the mandible, skull, and long bones known as osteomas, and abnormal growths of fibrous tissue called desmoid tumors.
Other important features include thyroid tumors, epidermal cysts, and dental abnormalities like supernumerary teeth. Finally, some individuals might develop pigmented lesions in the retina, known as congenital hypertrophy of the retinal pigment epithelium.
Another chapter in the FAP book is Turcott syndrome. In this chapter, intestinal polyps come along with central nervous system tumors, specifically medelloblastomas and glioblastomas.
Now moving on to clinical manifestations, in the early stages, the polyps are usually small and harmless, so symptoms often don't show up.
But as they grow and increase in number, they tend to get irritated and bleed, which can result in rectal bleeding or blood in the stool.
In severe cases, chronic bleeding can result in anemia. Other manifestations include diarrhea, frequent bowel movements, abdominal pain, cramping, and mucous discharge from the rectum.
Some people with FAP also experience symptoms related to polyps in other areas of the digestive tract or from other manifestations of the condition.
For example, polyps in the small intestine might cause abdominal pain or even obstruction, while desmoid tumors in the abdomen can cause pressure on nearby organs.
Diagnosis primarily relies on colonoscopy, which uses a flexible tube with a camera to look inside the colon. In FAP you'll see 100s or even thousands of polyps lining the colon wall.
During the procedure, it's important to obtain samples for biopsy to confirm these growths are benign polyps and not cancer.
Finally, if there's a family history of FAP genetic testing plays a key role in identifying APC mutations before any symptoms appear.
Since there are too many polyps to remove individually and the risk of cancer is so high, the standard treatment is surgical removal of the colon and rectum, typically during the late teens or early twenties.
All right, as a quick recap. Familial adenominous polyposis or FAP is an autosomal dominant condition that starts when a person inherits one mutated APC gene.
At first, the other gene produces enough APC protein to control the cell growth, but once the second APC gene mutates, no functional APC proteins are left, so the cell loses all control, letting beta cattenin drive cells to grow and divide without limits.
This uncontrolled growth causes cells to pile up into adenomatous polyps, which can progress to cancer if not treated.