Familial Adenomatous Polyposis

Background

Familial adenomatous polyposis (FAP) is an inherited genetic condition that causes the growth of
hundreds to thousands of polyps (abnormal mushroom-shaped growths of tissue) in a patient's lower
intestine (including the colon and rectum). Polyps may be seen in a patient's upper intestine as well.
About one in 30,000 people is affected with FAP.

Polyps usually begin to grow in patients at about age 10 to 12. Initially, these polyps do not cause
symptoms in most patients. However, they greatly increase the risk of colon cancer, in which cells in the
colon divide uncontrollably and develop into tumors. Almost all patients with FAP develop colon cancer
by age 40.

FAP is known to be caused by mutations in a gene called adenomatous polyposis coli or APC (APC). This
gene contains the genetic code for making the APC protein, which regulates growth in normally
functioning cells. Mutations in the APC gene can result in an abnormal APC protein that cannot properly
control cell growth. This leads to the formation of polyps in patients with FAP.

If the polyps are removed before cancer develops, patients may greatly reduce their risk of developing
cancer. If colon cancer does develop, it can be life-threatening. However, it can be treated in a number
of ways, including surgery, radiation therapy, and chemotherapy.

Risk Factors

Because familial adenomatous polyposis (FAP) is inherited, a family history of the disease is the main risk
factor.

About 6% of people with Ashkenazi Jewish Heritage have a mutant variant of the APC gene (an amino
acid substitution at one position in the gene) that may increase the risk of developing colon cancer by
10-20%.

Causes

General: Familial adenomatous polyposis coli (FAP) is known to be caused by mutations in a gene called
adenomatous polyposis coli or APC. This gene contains the genetic code for making the APC protein,
which normally functions in cells to regulate cell growth. Mutations in the APC gene can result in an
abnormal APC protein that cannot properly control cell growth. This leads to the formation of polyps in
patients with FAP.

More than 700 different mutations in the APC gene may lead to FAP. The most common disease-causing
mutations in the APC gene result in the production of a shortened version of the APC protein that is
unable to function normally. Some mutations in the APC gene lead to more severe forms of FAP (more
polyps and faster onset) than other mutations.

Inheritance: Most cases of familial adenomatous polyposis (FAP) are inherited, meaning that a defective
gene was transmitted from a parent to the child. Patients with FAP may have a mutation, or genetic
error, in a gene called adenomatous polyposis coli or APC. Individuals receive two copies of most genes
(one from the mother and one from the father). In patients with FAP, at least one copy of the APC gene
appears to be defective.

If an individual has a parent with one mutant APC gene, that individual has a 50% chance of inheriting a
mutant APC gene and developing the disease. Because only one defective gene is needed for FAP to
develop, the disease is considered to follow an autosomal dominant inheritance pattern.

Some cases of FAP follow an autosomal recessive inheritance pattern, meaning two abnormal copies of
a gene are needed for the condition to develop. The recessive form of FAP (also called MYH-associated
polyposis) is caused by mutations in the MUTYH gene. This gene makes a protein called MYH
glycosylase, which is an enzyme that repairs mistakes in DNA.

Random occurrence: About a third of cases of FAP are not inherited, but instead result from a
spontaneously arising mutation in the APC gene in the egg, sperm, or in early embryonic development.

Other: FAP may also be caused by mutations in the MUTYH gene. This gene makes a protein called MYH
glycosylase, which is an enzyme that repairs mistakes in DNA. Mistakes may occur in DNA during cell
division and these mistakes may cause other genes to undergo mutations and to function incorrectly. In
individuals with MUTYH mutations, mistakes may accumulate in the DNA because they are not properly
repaired. Over time, these mutations may cause cells to grow abnormally, which could eventually lead
to cancer.

About two-thirds of patients with Turcot syndrome have mutations in the APC gene. Turcot syndrome is
a condition that is related to FAP. Patients with Turcot syndrome develop colorectal cancer along with
brain cancer.

Signs and Symptoms

Patients with familial adenomatous polyposis coli (FAP) experience the growth of hundreds to
thousands of polyps (an abnormal mushroom-shaped growth of tissue) in the lower intestine (including
the colon and rectum). Growth of polyps may be seen in a patient's upper intestine as well. The number
of polyps usually increases with age and they typically grow from 1-2 to 4-5 millimeters in size.

Most patients do not experience any symptoms early on as a result of the polyps. As the polyps grow in
size, they may bleed and cause some patients to experience blood in the stool. Other gastrointestinal
problems may occur, including diarrhea and abdominal pain. The polyps have a high likelihood of
becoming cancerous.

In some patients, polyps may also grow in the upper intestine (duodenum) or even in the stomach.
These polyps have a much lower risk of becoming cancerous than polyps in the colon or rectum.

A large number of patients with FAP develop small "freckles" at the back of the retina (also called
congenital hypertrophy of the retinal pigment epithelium). These pigmented lesions are considered one
of the first signs of the disease and can sometimes be observed in infants. However, these freckles are
benign (harmless) and do not cause any symptoms. Some patients with FAP may also develop lumps or
bumps on the bones, which may affect any part of the skeleton. Cysts, or fluid filled sacs, may also
develop on the skin.
Diagnosis

Familial adenomatous polyposis (FAP) is usually diagnosed by checking for the presence of polyps in a
patient's colon. There are several methods that can be used to screen for polyps. Patients who have a
family history of FAP are encouraged to undergo screening early on (in their teens) so that polyps can be
detected before cancer has a chance to develop.

Colonoscopy: Doctors may perform a colonoscopy to check for polyps in the colon. In a colonoscopy, a
flexible tube with a light attached (called an endoscope) is inserted through a patient's anus. The
endoscope can transmit images of the patient's colon to the doctor so that any polyps can be observed.

Barium enema: To visualize the entire large intestine, a liquid dye called barium may be used to fill and
coat a patient's intestine. Then, a doctor uses X-rays to take pictures of the patient's intestine. The
barium will cause any polyps along the lining of the intestine to appear as dark areas on the X-ray image,
allowing the polyps to be observed.

Computed tomography: An imaging technique called a computed tomography (CT) scan may be used to
observe polyps in a patient's colon. A CT scan is a noninvasive imaging technique that uses a series of X-
rays to create detailed three-dimensional images of the inside of a patient's body. Polyps can then be
detected in these images.

Genetic testing: Mutations in the APC gene or MUTYH gene are known to cause FAP. Genetic tests can
be used to check for these mutations and diagnose FAP. These tests may confirm a diagnosis if there is a
family history of FAP or if symptoms of FAP are present.

Complications

Colon cancer: The most common complication in patients with familial adenomatous polyposis (FAP) is
colon cancer. About one percent of all cases of colon cancer are due to FAP, and all patients with FAP
develop colon cancer by the time they are 40. Colon cancer is a disease in which the growth of cells in
the colon has become deregulated, such that they divide uncontrollably and develop tumors. Colon
cancer is a potentially life-threatening condition, and further complications may result when tumor cells
metastasize (spread) to other tissues. Prognosis is worst in cases where the tumor has metastasized to
other areas of the body such as the liver.

Desmoid tumors: Some patients with FAP develop tumors that are not cancerous, called desmoid
tumors. These fibrous tumors are similar to scar tissue, and they often develop in the abdomen. Even
though they are not cancerous, they may cause pain if they grow large enough to block a blood vessel or
the bowel. Desmoid tumors may be surgically removed but usually grow back after removal.

Treatment

If polyps are found at an early stage before cancer has a chance to develop, they can be surgically
removed. Patients with familial adenomatous polyposis (FAP) who have polyps removed early in the
disease have a very high chance of not developing cancer (near 100%).

There are often too many polyps present to remove each one individually. Depending on the extent of
the disease, a patient will need to have the entire colon removed (a colectomy) or the colon, rectum,
and in some cases the anus removed (a proctocolectomy).
In a colectomy, the colon is removed, and the small intestine is surgically connected directly to the anus.
In a proctocolectomy in which the colon and rectum are removed, a small pouch is inserted to connect
the small intestine to the anus and allow the passage of waste. In a proctocolectomy in which the colon,
rectum, and anus have been removed, a portion of the intestine may be brought out through a hole in
the abdominal wall, so waste can be directly delivered to an external bag.

Patients who undergo surgery need to have frequent checkups (every three to twelve months) to ensure
that polyps do not begin to form in other parts of the digestive tract, such as the stomach, upper third of
the small intestine (duodenum), or rectum (if it was not initially removed). If new polyps are observed,
patients may need to undergo additional surgeries.

In patients who do not have polyps removed promptly and as a result develop cancer, a number of
treatments are available to help to control the tumor growth. Tumors may be removed surgically or
cancer cells may be killed with radiation or with drugs (such as irinotecan, oxaliplatin, and 5-
fluorouracil). Patients who develop cancer should consult with a physician to determine the best
therapy. If treated at an early stage, patients who develop colon cancer have a good chance of surviving.

Integrative Therapies

Note: Currently, there is a lack of scientific data on the use of integrative therapies for the treatment or
prevention of familial adenomatous polyposis (FAP). The therapies listed below have been studied for
related conditions, such as colon cancer, and should be used only under the supervision of a qualified
healthcare provider, and not as a replacement for other proven therapies or preventive measures.

Good scientific evidence:

Lactobacillus casei: There is recent evidence that supplementation with Lactobacillus casei may help
reduce the recurrence of colorectal tumors in patients who have previously undergone surgery for colon
cancer. Probiotics are generally regarded as safe for human consumption. Long-term consumption of
probiotics is considered safe and well-tolerated.

Unclear or conflicting scientific evidence:

Omega-3 fatty acids: Omega-3 fatty acids are commonly taken by cancer patients. Although preliminary
studies report that growth of colon cancer cells may be reduced by taking fish oil, effects on survival or
remission have not been measured adequately. Omega-3 fatty acids may increase the risk of bleeding,
although there is little evidence of significant bleeding risk at lower doses. Very large intakes of fish
oil/omega-3 fatty acids may increase the risk of hemorrhagic (bleeding) stroke. High doses have also
been associated with nosebleed and blood in the urine. Fish oils appear to decrease platelet aggregation
and prolong bleeding time, increase fibrinolysis (breaking down of blood clots), and may reduce levels of
von Willebrand factor.

Psyllium: According to early research, diets that include psyllium may reduce the risk for colon cancer.
More studies are needed to determine whether psyllium can help prevent colon cancer. Serious allergic
reactions including anaphylaxis, difficulty breathing/wheezing, skin rash, and hives have been reported
after the ingestion of psyllium products. Less severe hypersensitivity reactions have also been noted.
Cross-sensitivity may occur in people with allergy to English plantain pollen (Plantago lanceolata), grass
pollen, or melon.
Soy: Soy (Glycine max) contains compounds that have shown efficacy against tumors. Genistein, an
isoflavone found in soy, has been found in laboratory and animal studies to possess anti-cancer effects,
such as blocking new blood vessel growth (anti-angiogenesis), acting as a tyrosine kinase inhibitor (a
mechanism of many new cancer treatments), or causing cancer cell death (apoptosis). In contrast,
genistein has also been reported to increase the growth of pancreatic tumor cells in laboratory research.
There is currently insufficient scientific evidence to determine if dietary intake of soy affects the risk of
developing colon cancer. Study results are mixed and more research is needed before a
recommendation can be made.

Vitamin E: Reliable scientific evidence indicating that vitamin E is an effective treatment for any specific
type of cancer is currently lacking. There is insufficient scientific evidence to determine if vitamin E
prevents colon cancer. In patients with previous colon cancer, a combination of vitamins A, C, and E has
been reported to reduce the risk of developing recurrent colon cancer. Preventive benefits have also
been suggested in those with no prior colon cancer when vitamin E is used in multivitamin preparations,
but not when Vitamin E is used alone. Results from the Women's Health Study report no overall
reduction in cancer risk with daily use of vitamin E, although this study was not large enough to look at
colon cancer specifically. Additional research is necessary in this area before a firm conclusion can be
reached. Caution is merited in people undergoing treatment with chemotherapy or radiation, because it
has been proposed that the use of high-dose antioxidants may actually reduce the anti-cancer effects of
these therapies. This remains an area of controversy and studies have produced variable results.
Patients interested in using high-dose antioxidants such as vitamin E during chemotherapy or radiation
should discuss this decision with their medical oncologist or radiation oncologist. Caution is advised
when taking vitamin E supplements, as numerous adverse effects including an increased risk of bleeding
and drug interactions are possible.

Prevention

There are currently no known ways to prevent familial adenomatous polyposis coli (FAP). However, early
screening with a colonoscopy may reduce the risk of developing colon cancer.

Genetic counseling is available to parents. Individuals from high-risk populations, or those with family
histories of FAP, may meet with genetic counselors to determine whether they carry a genetic mutation
linked to FAP. Carriers can be determined through detailed family histories or by genetic testing. Known
carriers of FAP may undergo genetic counseling before they conceive a child. Genetic counselors can
explain the options and the associated risks of various tests, such amniocentesis, chorionic villus
sampling (CVS), or preimplantation diagnosis.