Familial adenomatous polyposis
| Familial adenomatous polyposis | |
|---|---|
| Specialty | Oncology, gastroenterology  |
Familial adenomatous polyposis (FAP) is an inherited condition in which numerous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into [colorectal cancer|colon cancer] occurs 100% of the time when not treated.
Signs and symptoms
From early adolescence and onwards, patients develop hundreds to thousands of polyps. These may bleed, leading to the presence of blood in the stool. If the blood is not visible, it is still possible for the patient to develop anemia due to gradually developing iron deficiency. If malignancy develops, this may present with weight loss, altered bowel habit, or even with metastasis in the liver or elsewhere.
The genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g. of the duodenum and stomach. Other signs that may point at FAP are pigmented lesions of the retina ("congenital hypertrophy of the retinal pigment"), jaw cysts, sebaceous cysts, and osteomata (benign bone tumors). The combination of polyposis, osteomas, fibromas and sebaceous cysts is termed Gardner syndrome (with or without abnormal scarring).
Diagnosis and treatment
Making the diagnosis of FAP before the development of colon cancer is important insofar as not only the individual but also affected family member's survival is at stake. Colonoscopy is considered the diagnostic test of choice as it can provide not only a quantitation of polyps throughout the colon but also a histologic diagnosis. Barium enema and virtual colonoscopy can suggest the diagnosis of FAP.
Once the diagnosis of FAP is made close [colonoscopy|colonoscopic] surveillance with polypectomy is required. [Prophylaxis|Prophylactic] [colectomy] is indicated if more than a hundred polyps are present, there are severely dysplastic polyps, or multiple polyps larger than 1 cm are present. When partial colectomy is performed, colonoscopic surveillance of the remaining colon is necessary as the individual still carries significant risk of developing colon cancer.
Blood tests (liver enzymes) and ultrasound of the abdomen are often performed to rule out metastasis to the liver.
Genetic testing provides the ultimate diagnosis in 95%; genetic counseling is usually needed in families where FAP has been diagnosed. Testing may also aid in the diagnosis of borderline cases in families that are otherwise known to have the FAP mutation.
Pathophysiology
FAP is due to mutations in the APC gene, which is located on the fifth chromosome (5q21-q22), or in the MUTYH gene located on chromosome 1 (p34.3-p32.1).
APC is a tumour suppressor gene, acting as a "gatekeeper" to prevent development of tumours. Mutation of APC also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer.
Although the polyps are inherently benign, the first step of the two-hit hypothesis has already taken place: the inherited APC mutation. Often, the remaining "normal" allele is mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in p53 or KRAS) to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated epithelial cells.
The normal function of the APC gene product is still being investigated; it is present both the cell nucleus and the membrane. The canonical tumor-suppressor function of Apc is suppression of the oncogenic protein beta-catenin. However, other tumor-suppressor functions of Apc may be related to cell adherence and cytoskeleton organization.
MUTYH encodes DNA repair enzyme MYH glycosylase. During normal cellular activities, guanine sometimes becomes altered by oxygen, which causes it to pair with adenine instead of cytosine. MYH glycosylase fixes these mistakes by base excision repair, such that mutations do not accumulate in the DNA and lead to tumor formation. When MYH glycosylase does not function correctly, DNA errors may accrue to initiate tumorigenesis with a clinical presentation similar to that in patients with Apc mutations.
Genetics
Familial adenomatous polyposis can have different inheritance patterns and different genetic causes. When this condition results from mutations in the APC gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.
Mutations in the MUTYH gene are inherited in an autosomal recessive pattern, which means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.
Prenatal testing is possible if a disease-causing mutation is identified in an affected family member; however, prenatal testing for typically adult-onset disorders is uncommon and requires careful genetic counseling.
Animal Models
The "ApcMin" mouse model was isolated in 1990 and harbors an Apc allele with a stop codon at position 850. Heterozygosity for this mutation results in a fully penetrant phenotype, with mice on a sensitive background developing over 100 tumors in the intestinal tract. Many other models have since appeared, including a model of attenuated FAP (the 1638N model) and several conditional mutants that allow for tissue-specific or temporal ablation of gene function.
In 2005, the "ApcPirc" rat model was isolated with a stop codon at position 1137. In constrast to the mouse models where >90% of tumors form in the small intestine, the Pirc rat forms tumors preferentially (>60%) in the large intestine, similar to the human clinical presentation. Genetic screens, pharmacological testing, and other areas of research have allowed for discoveries in the mouse and rat to be applied to the study of human FAP.
Epidemiology
The incidence of the mutation is between 1 in 10,000 and 1 in 15,000 births. By age 35 years, 95% of individuals with FAP have polyps. Without colectomy, colon cancer is virtually inevitable. The mean age of colon cancer in untreated individuals is 39 years (range 34-43 years).
Treatment
Treatment for FAP will require frequent surveillance colonoscopy investigations; in a number of cases, removal of the colon is necessary to prevent the development of malignancy, or to cure it. If a large part of the bowel is removed, construction of an ileostomy or ileo-anal pouch may be necessary.
Various medications are being investigated for slowing malignant degeneration of polyps, most prominently the non-steroidal anti-inflammatory drugs (NSAIDs).
References
- Gardner EJ. A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum. Am J Hum Genet 1951;3:167-76. PMID 14902760