Familial Adenomatous Polyposis Health Article

Definition

Familial adenomatous polyposis is an inherited condition that typically presents with extensive adenomatous polyps of the colon. These polyps often develop into colorectal cancer in early adult life. Other symptoms are often present as well. These signs include polyps in the upper gastrointestinal tract, malignancies in the brain or thyroid, pigmented retinal lesions, and osteomas.

Description

Familial adenomatous polyposis (FAP) was first clearly described as a dominantly inherited colorectal cancer susceptibility by Lockhart-Mummery in an article published in 1925. FAP has since served as a paradigm for hereditary cancer and has taught much about the diagnosis, surveillance, and management of colon cancer. It is one of the most clearly defined and well understood of the inherited colon cancer syndromes. FAP is thought to account for approximately 1% of all cases of colorectal cancer.

FAP is a disorder that is characterized by the development of hundreds to thousands of glandular colorectal tumors called adenomas or adenomatous polyps, meaning that they are benign growths made of the tissue that lines the inside of the colon. They are described as polyps because they protrude from mucous membranes. In FAP, these tumors generally develop by the second or third decade of life. They are found in the internal lining of the colon and the rectum, with a particular affinity for the left side of the colon or the rectosigmoid. By themselves, these polyps are benign but they have the ability to become malignant, leading to colorectal cancer. If the polyps are not treated properly, it is almost certain that a person affected with FAP will develop colorectal cancer by the age of 40.

Other clinical findings that may be associated with FAP include polyps in the upper gastrointestinal tract, extraintestinal manifestations such as osteomas and epidermoid cysts, desmoid formation, retinal lesions, and malignant changes in other organs. Symptoms are thought to manifest anywhere between the ages of 16 and 50 years.

FAP is also known as familial polyposis coli (FPC) and adenomatous polyposis coli (APC). Gardner syndrome and Turcot syndrome are variants of FAP. Gardner syndrome is used to describe patients with FAP and the extracolonic symptoms of osteomas, soft tissue tumors, desmoids, and dental abnormalities. Turcot syndrome is used when FAP is seen in conjunction with tumors of the central nervous system called medulloblastomas (cerebral tumors that occur in childhood). Attenuated FAP (AFAP) is another variant of FAP. In this condition, individuals present with fewer polyps, usually fewer than 100 in number and often in the right colon. Patients with AFAP may have a later onset of cancer than those with classic FAP.

Genetic profile

FAP is inherited in an autosomal dominant pattern; thus, an affected person has a 50% chance of passing the disease on to each of his or her children. It is almost 100% penetrant, meaning that nearly everyone who carries the gene mutation will show signs of the disorder. The majority of patients with FAP inherit the mutation from one of their parents. However, in approximately 25% of cases, there is no family history of the disorder and FAP occurs because of a new mutation in the affected individual.

The majority of cases of FAP are due to mutations of the APC gene, located on the long arm (or "q" arm) of chromosome 5. This gene encodes a protein that is important in cell adhesion and signal transduction. More than 300 different APC mutations have been described in FAP patients. Most APC mutations seen in individuals with FAP result in translation of a protein that is shorter than normal. This shortened protein cannot function properly.

Studies have shown that the type and location of the APC mutation seems to correlate to the clinical symptoms that a person manifests. For example, if the mutation is located near the center of the gene, colonic polyps tend to be more dense and numerous. A mutation towards the ends of the gene often leads to polyps that are fewer and more sparse, as in attenuated FAP. Additionally, mutations at one particular end (the 3null end) of the APC gene seem to be associated with a higher risk of desmoid formation. However, it is known that family members who carry identical mutations often have different clinical features. This suggests that modifying genes and/or environmental factors also influence the expression of the APC gene mutation.

The APC gene is a tumor suppressor gene, meaning that its function is to control cell growth. When APC is mutated, it does not function correctly and allows cells to grow out of control. This results in tumors that may lead to cancer. Carriers of mutations in APC inherit a germline mutation in one allele of the gene. Thus, in every one of their cells, one gene does not make the APC protein but the corresponding gene on the other chromosome continues to produce the functional protein. Thus, tumor suppression continues. However, if a somatic mutation occurs in the remaining functional gene, no APC protein is made, tumor suppression fails, and tumors develop. These somatic mutations occur in various parts of the body at various times, leading to multiple tumors forming in distinct parts of the body over a period of time. In the case of FAP, many of these tumors are confined to the colon but can occur in other organs as well.