Hereditary Cancer & Genetics: About Familial Adenomatous Polyposis (FAP)

1. What is familial adenomatous polyposis (FAP)?

Familial adenomatous polyposis (FAP) is a colon cancer syndrome caused by mutations in the APC gene located on chromosome 5. According to the National Institutes of Health, FAP affects approximately 1 in 30,000 individuals, characterized by the development of hundreds or thousands of colonic polyps (polyposis) occurring when a person is in his/her 20s or 30s. The condition progresses to colon cancer in almost every case.

For an individual with the FAP syndrome, colon polyps typically begin to appear at an average age of 16 (but can range from as young as 7 to as old as 36); and the average age of colon cancer diagnosis is 39.

• FAP is also associated with a risk for upper gastrointestinal polyps and malignancies.
• Duodenal polyps are present in up to 90 percent of patients, but only 4 to 12 percent of these polyps will progress to malignancy.
• Gastric fundic gland polyps are also frequently seen during upper endoscopy but have little potential for malignancy.
• Much smaller increases in risks of other cancers [such as thyroid, pancreatic, brain (medulloblastoma) and hepatobiliary tumors] may exist in certain families with a history of FAP.
• An additional group of findings, previously known as Gardner’s syndrome, are now thought to be part of the FAP spectrum and may or may not be present in an individual with FAP. These include sebaceous cysts, lipomas, fibromas, facial bone osteomas, and/or dental anomalies.
• Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is clinically insignificant but is a useful diagnostic marker for the FAP syndrome if present in a family. CHRPE is characterized by pigmented lesions in the retina of the eye that can be detected via funduscopic examination.
• Desmoid tumors are present in approximately 10 percent of individuals with classic FAP. The particular symptoms displayed by individuals show considerable variability within a family; although, in certain cases, knowledge of the particular gene mutation may help predict the chance of desmoids occurring.

FAP follows an autosomal dominant pattern of inheritance. An autosomal dominant inheritance pattern means that only one copy of the gene, which may be inherited from either parent, is sufficient for a person to be affected. Approximately 25 percent of cases occur in the absence of a family history of FAP (i.e., due to a new (de novo) mutation in an individual). Both men and women who carry an APC gene mutation have a 50 percent chance of passing that mutation on to each child (independent of the status of the other children) conceived.

2. If I am diagnosed with FAP, what can be done about it?

Individuals diagnosed with FAP are advised to seek medical care at a comprehensive clinical care center with experience in management of the condition.

• For those with diagnosed FAP or suspected classic FAP, an annual flexible sigmoidoscopy is recommended beginning at age 10 to 15 years or earlier if symptoms develop.
• Once polyposis is established, a complete annual colonoscopy is necessary until prophylactic surgery is undertaken. If no polyps are detected, the frequency of sigmoidoscopy may be reduced to:
  • every 2 years after age 24,
  • every 3 years after age 34, and
  • every 3 to 5 years after age 44.
• In the absence of independent risk factors, an individual may follow average risk guidelines only if conclusively demonstrated through genetic testing not to be at-risk for FAP or if no polyps have been detected by age 50. Average risk guidelines include colonoscopy every 5 to 10 years beginning at age 50.
• For individuals with clinically evident classic FAP, prophylactic colectomy is the treatment of choice, usually in the teen years or early 20s or if dense polyposis or severe dysplasia is present. A prophylactic colectomy is a type of surgery in which the entire colon is removed to prevent a new colon cancer from occurring in the future. The optimal age for prophylactic surgery should be chosen in consideration of previous colonoscopic findings and symptomology, if any, as well as psychological and social factors. Such surgery is not generally performed on a polyp-free colon. If the rectum is left intact, annual endoscopy of the remaining rectum is necessary following surgery.

Preliminary studies have suggested the long-term use of oral chemopreventive agents, such as cyclooxygenase-2 (COX-2) inhibitors (e.g., Celebrex©, Bextra©) and sulindac, aspirin, folate, and calcium, may be effective in reducing the incidence of adenomatous polyps and their subsequent progression to colorectal cancer. Studies have suggested a benefit for individuals with familial adenomatous polyposis, though recent studies have also shown increased heart risks associated with some COX-2 inhibitors. Chemoprevention should not replace screening for colorectal cancer nor should it replace measures known to promote good health, such as smoking cessation, regular physical activity, an increase in dietary fiber, reduction of fat intake, and weight control.

Annual physical and dermatologic examinations are recommended, including palpation of the liver and thyroid and review of symptoms. Palpation is a method of assessment in which the area is examined by touch. Some groups have proposed diagnostic measures, such as an annual serum alpha-fetoprotein and perhaps hepatic ultrasound in children with classic FAP in order to screen for hepatoblastoma. Ophthamologic examination may be useful to assess for congenital hypertrophy of the retinal pigment epithelium (CHRPE).

3. What is attenuated familial adenomatous polyposis (AFAP)?

Attenuated familial adenomatous polyposis (AFAP) is a milder form of FAP that, like classic FAP, is due to mutations in the APC gene. Attenuated FAP differs from the classical form of FAP in the number of colonic adenomas (polyps that are at a precancerous stage in which they may or may not develop into cancerous cells) that develop (usually less than 100; average 30) and the average age of onset for colorectal cancers (55 for attenuated FAP as opposed to 40 for classical FAP). The attenuated form of FAP has been associated with mutations near the beginning (5-prime) or the end (3-prime) of the APC gene. Individuals are encouraged to obtain medical records documenting the number and type of colon polyps they, themselves, have and the number and type of colon their relatives have; this knowledge may help differentiate between FAP and AFAP in a family.

AFAP may be associated with small, increased risks for upper gastrointestinal (duodenal, gastric fundic gland, and hepatobiliary) polyps and/or cancers. Other findings seen in classic FAP families, such as desmoid tumors, bone osteomas, and congenital hypertrophy of the retinal pigment epithelium (CHRPE), are only rarely seen in AFAP. The particular symptoms displayed by an individual show considerable variability within a family; although knowledge of the particular gene mutation may, in certain cases, help predict the chances that various symptoms may occur in an individual.

4. If I am diagnosed with AFAP, what can be done about it?

For those with diagnosed or suspected AFAP, the first colonoscopy should be performed in the late teen years. As long as no polyps are detected, colonoscopies should be repeated every 2 to 3 years. Once adenomatous polyps have been established, more frequent, complete colonoscopies are necessary as directed by an individual’s physician. Colonoscopy is favored over sigmoidoscopy, given the right-sided tendency of adenomas in individuals with AFAP.

For those with AFAP, treatment depends largely on the polyp burden and location. In those with few adenomas, polypectomy and management with a cyclooxygenase-2 inhibitor may be sufficient. Surgical evaluation and counseling regarding prophylactic colectomy and ileorectal anastomosis is recommended, especially for those with significant polyposis, those who are age 40 and over, or those for whom colonoscopy is technically difficult.

5. What does it mean to have AFAP?

The exact lifetime risk for colorectal cancer (CRC) in an individual with AFAP has yet to be defined but may be high. Some people with AFAP, however, do not get cancer; so this gene is not a guarantee for cancer. People with AFAP do not appear to have greatly increased risks for other cancer types. Features other than CRC, however, may be present in some families. [See Question Three: What is attenuated familial adenomatous polyposis (AFAP)?]

6. What causes FAP and AFAP?

Both FAP and AFAP are caused by mutations in the APC gene.

7. How are FAP and AFAP inherited?

Genes come in pairs. One of each pair is inherited from the mother the other from the father. In both FAP and AFAP, only one altered copy is necessary to have increased risks. Therefore, a person who has AFAP may have inherited his/her altered gene from his/her mother or father.

A person who has inherited an APC gene mutation has a 50 percent chance of passing the mutation on to his/her child. If the child inherits the mutation, she/he will be at increased risk of developing cancer. If the child does not inherit the mutation, her/his cancer risk (in most cases) will be equal to that of the general population. In the general population, the average lifetime risk for developing colorectal cancer is about 6 percent.

8. What genetic testing is available for FAP and AFAP?

In the past, genetic testing for FAP was performed using what is called the protein truncation test (PTT), which detects approximately 70 percent of genetic mutations. Now, the entire APC gene may be evaluated, without first doing PTT, by reading the entire gene. This is called gene sequencing.

For individuals who have tested negative on APC gene sequencing, new genetic testing for APC gene mutations, called Southern blot, is now available. This testing looks for gene changes where large portions of the gene may be missing or rearranged. These changes may be missed or undetectable on more traditional gene sequencing. If you have had negative APC testing in the past, we encourage you to make an appointment with us at the Clinical Genetics Service to discuss whether further testing makes sense for you.

If someone else in your family has already tested positive, you may be tested for the specific mutation found in their sample. If you have tested negative for a mutation that’s known to run in your family, no further testing is needed.

9. If I am tested for FAP and AFAP, what are the possible results?

• A positive result means that a mutation was detected in the APC gene, and that this mutation is most likely responsible for the colon cancers in your family members.
• A negative result means that a mutation was not detected. Chances are that the cancers in your family due to APC are much lower but cannot be ruled out!
• In addition there is a chance of an ambiguous result. In other words, a variant, a genetic change of unknown significance may be detected. It is useful to discuss this outcome with a genetic counselor.

10. What are the possible benefits and risks of genetic testing?

You should think about the following benefits and risks before you undergo genetic testing.

Benefits

• Genetic test results may allow for a better assessment of your cancer risk and that of your relatives. If the results are positive, doctors can screen earlier and more often (see above) for colorectal cancer and other associated cancers. If the results are negative, screening recommendations will be determined by your medical and family history.
• If a mutation is identified, informative genetic testing and/or early cancer screening can be offered to other at-risk family members. Under these circumstances if your relative tests negative, it may mean that he/she does not have increased cancer risks.
• There is no physical risk involved in genetic testing other than that of a routine blood draw.
• Some people are curious about what caused their cancer. For these people, testing may provide a psychological benefit since it may provide an explanation for why they developed colon cancer.

Risks

• Genetic testing can be emotionally difficult regardless of the results.
• There is also the theoretical possibility of employment, health or life insurance discrimination based on genetic test results. In theory, insurers could seek higher premiums or cancel/deny policies for individuals with “pre-existing” genetic conditions. In New York State, a person’s genetic test results cannot be given to anyone else without the tested person’s written permission. At present, we are not aware of any instances of genetic discrimination against families who have received genetic testing at Memorial Sloan-Kettering.

11. What if I have a family history of colorectal cancer but don’t want to undergo genetic testing?

Even if you don’t want to take part in a study and/or receive genetic testing, you should talk to your doctor about your family history of colorectal cancer. If any one of your close relatives has had colorectal cancer, you have an increased chance of developing colorectal cancer as well. You may also consider genetic counseling, even without genetic testing, to further discuss these risks. Speak with your doctor or a genetic counselor about your family history of colorectal cancer, and discuss appropriate screening recommendations to lower your risk of developing this disease.

12. What is MYH?

MYH is a gene that research findings suggest accounts for some families with colorectal cancer (CRC). It has been implicated only very recently and has not yet been well-studied. For this reason, there is little information as to what it means to carry a mutation in this gene. Preliminary studies have suggested that the clinical consequences of having 2 MYH mutations may be very similar to having AFAP. The major difference between AFAP and MYH may be the mode of inheritance — in other words, the way it is passed on in families. [See Question 13: How is an MYH mutation inherited?]

MYH should be considered in an individual with:

• Classic FAP features and a negative test result for the APC gene, or
• From 15 to 1,000 colonic adenomatous (precancerous) polyps, or
• A family history of colon cancer in only one generation in persons less than age 60 years and with multiple adenomatous polyps. In particular, those families who have already tested negative for mutations in the APC gene (more commonly associated with AFAP) should be considered.

13. How is an MYH mutation inherited?

The predisposition may run in families in a pattern different from other hereditary colorectal cancer predispositions. Some preliminary data show that the MYH gene is transmitted in an autosomal recessive mode. This means that an individual may need TWO copies of a MYH-mutated gene in order to have the predisposition. One copy must come from each parent. Therefore, even if an individual with CRC is found to have a mutation in both copies of MYH, this person’s children may not be at high risk. This has yet to be fully established however. Right now, the clinical significance (if any) of carrying just one copy of MYH is not fully understood.

14. What are the possible benefits and risks of MYH gene testing?

You should think about the following benefits and risks before you undergo genetic testing.

Benefits

• Currently the benefits of MYH testing are not known.
• It is possible that in the future, genetic test results may allow for cancer screening recommendations more suited to an individual’s specific risk profile.
• There is no physical risk involved in genetic testing other than that of a routine blood draw.
• Some people are curious about what caused their cancer. For these people, testing may provide a psychological benefit since it may provide an explanation for why they developed colon cancer.

Risks

• Genetic testing can be emotionally difficult regardless of the results.
• There is also the theoretical possibility of employment, health or life insurance discrimination based on genetic test results. In theory, insurers could seek higher premiums or cancel/deny policies for individuals with “pre-existing” genetic conditions. In New York State, a person’s genetic test results cannot be given to anyone else without the tested person’s written permission. At present, we are not aware of any instances of genetic discrimination against families who have received genetic testing at Memorial Sloan-Kettering.

The decision whether to have genetic testing is a personal one. Individuals and families must weigh the risks and benefits of testing in light of their own personal circumstances.