Familial adenomatous polyposis

What is familial adenomatous polyposis?

Familial adenomatous polyposis, also known as familial polyposis coli, adenomatous polyposis coli, or Gardner syndrome, is seen in approximately one in 8,000 individuals. The term Gardner syndrome has sometimes been used to refer to patients who manifest extracolonic features.

In its classic form, FAP is characterized by the following:

• Polyposis – the development of multiple benign (noncancerous) adenomatous polyps (greater than 100) in the colon and rectum, which are described as having a “dense carpet-like appearance” on colonoscopy or sigmoidoscopy.
• Early age of onset – polyps begin to develop at an average age of 16 years (range of seven to 36 years).
  • A nearly 100 percent risk of colorectal cancer in the absence of treatment for polyposis (colectomy, or surgery to remove the colon).
• An autosomal dominant pattern of inheritance (vertical transmission through either the maternal and paternal line).
• An increased risk of other health problems such as polyps in the upper gastrointestinal tract, osteomas (benign bony growths), epidermoid cysts (skin lesions), desmoid tumors (locally invasive tumors that grow aggressively and can be life threatening), congenital hypertrophy of retinal pigment (CHRPE) and dental abnormalities.
• An increased risk of thyroid, small bowel, pancreatic, and stomach cancers, brain tumors and hepatoblastoma (a childhood liver tumor).

A tumor suppressor gene called APC, located on chromosome #5, causes most cases of FAP. Virtually all persons who have a mutation in the APC gene that causes the classic form of FAP will develop colorectal polyps by the fourth or fifth decade of life (without intervention). However, the onset is variable. Consider the following:

Because FAP has such an early age of onset, cancer screening often begins in childhood. In addition, genetic testing of children at risk is a special consideration. Usually, genetic tests are not an option for persons who are considered minors unless there is some type of medical benefit available to justify testing. FAP is an autosomal dominant cancer genetic syndrome, which means that a child whose parent has the condition has a 50/50 chance of inheriting the familial APC gene mutation. There is an equally as likely chance the child will not inherit the familial APC mutation, which would spare the child from having to undergo annual examinations (i.e., sigmoidoscopy) if they were found to be mutation negative. Thus, since genetic testing can have an impact on medical management, genetic testing of children at risk of classic FAP is an option that can be considered.

The APC gene is a tumor suppressor gene, which usually has the job of controlling cell growth and cell death. Everyone has two APC genes (one on each chromosome #5). When a person has an altered, or mutated, APC gene, his or her risk of developing polyps and cancer increases.

Both copies of a tumor suppressor gene must be altered, or mutated, before a person will develop polyps or cancer. In FAP, the first mutation is usually inherited from either the mother or the father and is therefore present in all cells of the body, which is called a germline mutation. It is not until the second copy of the gene is mutated in, for instance, a colon cell, that a polyp develops. In order for a benign polyp to become malignant (cancerous), the polyp must acquire mutations in several additional growth control genes. Loss of both copies of APC is just the first step in the process of cancer development. What causes these additional mutations to be acquired is unknown. Possible causes include chemical, physical or biological environmental exposures or chance errors in cell replication. Since we do not know how to prevent these mutations from occurring, the treatment for classic FAP is a colectomy, a removal of the colon once polyps develop before they become cancerous.

It is important to remember that the APC gene is not located on the sex chromosomes. Therefore, mutations can be inherited from the mother or the father’s side of the family. In one-third of cases, the APC mutation is “de novo,” which means it was not inherited, but occurred for the first time in a family in the person with symptoms. Persons with de novo mutations still transmit them in the same inheritance pattern (autosomal dominant), which means there is a 50/50 chance for them to pass the mutation to a child (regardless of gender). 

What are genotype-phenotype variations?

Hundreds of mutations have been found throughout the APC gene. It has long been recognized that some families with APC mutations have different symptoms than others. Studies comparing symptoms in patients with different and similar APC mutations have been done to see if there are any correlations. A correlation between specific mutations and symptoms is called a “genotype-phenotype” correlation. Genotype-phenotype correlation studies for the APC gene have shown that the location of a mutation in the gene provides some information about the types of FAP health problems a person will have. For instance, mutations in certain parts of the gene are associated with an increased rate of desmoid tumors (locally invasive tumors that grow aggressively and can be life threatening), osteomas (benign bony growths) and epidermoid cysts (skin lesions). Where in the gene a mutation lies also provides some information about polyp burden (the number of polyps a person will develop). Even though some correlations exist, there is often variability of symptoms between people who have the same mutation. This variation is because factors other than the APC mutation (environmental factors, other genetic factors) contribute to the development of polyps and cancer. 

What is attenuated FAP?

An attenuated form of familial adenomatous polyposis has been identified. Individuals with AFAP develop fewer than 100 adenomatous polyps (average of 30 polyps) and the polyps are more likely to occur on the right side of the colon than in classic FAP. The risk of developing colon cancer is increased, but the average age of diagnosis is older (50 to 55 years of age) than in the classic form. Some of the other health problems associated with classic FAP also occur in the attenuated form; however, cases of congenital hypertrophy of the retinal pigment (CHRPE) and desmoid tumors are rarely seen.

Mutations in three specific areas of the APC gene have been associated with the AFAP phenotype. The polyp burden (number of polyps developed) and the risk of other FAP manifestations varies depending on in what area the mutation is located. One of these three areas of the gene is associated with a very variable number of polyps (ranging from two to 500). In families with such mutations, some relatives may have the AFAP phenotype whereas others have classic FAP.

Unlike FAP, not all persons with an AFAP-associated APC mutation will develop polyps, and the lifetime chance to develop polyps is unknown. The incidence of AFAP also is unknown, but thought to be about the same or less than classic FAP. 

What is a I1307K mutation?

One APC mutation in particular, called I1307K, is present in 6 percent of the Ashkenazi Jewish population. This mutation is associated with a 10 to 20 percent risk of colorectal cancer (slightly more than double the risk of someone else in the general population). However, people with this mutation do not present with the classic “carpet of polyps” in the colorectum seen in FAP.