Familial Adenomatous Polyposis (FAP) is a rare genetic disorder characterized by the development of numerous adenomatous polyps in the colon and rectum. Adenomatous polyps are precancerous growths that have the potential to become cancerous over time. If left untreated, individuals with FAP have a significantly increased risk of developing colorectal cancer (CRC) at a young age. FAP has an incidence of 1 case per 8,300 people, affects both sexes equally, and accounts for less than 1% of CRC cases. The prevalence in the European Union is estimated at 1 case per 11.300-37.600 inhabitants.
Familial adenomatous polyposis genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Key features of Familial Adenomatous Polyposis include:
- Polyposis: The hallmark of FAP is the development of hundreds to thousands of adenomatous polyps in the colon and rectum. These polyps can begin to appear in adolescence, increasing with age.
- Early Onset: The development of colorectal polyps occurs at an earlier age than in the general population, and if left untreated, colorectal cancer can develop in individuals with FAP by their 30s or 40s.
- Extracolonic Manifestations: FAP can also be associated with the development of polyps in other parts of the gastrointestinal tract, such as the stomach and small intestine. Additionally, extracolonic manifestations may include benign tumors and cysts in various organs.
- Genetic Basis: FAP is caused by mutations in the APC gene (adenomatous polyposis coli). The inheritance pattern is typically autosomal dominant, meaning that a person with a mutation in one copy of the APC gene has a 50% chance of passing the mutation to each of their children.
Due to the high risk of colorectal cancer in individuals with FAP, early detection and management are crucial. Management options include:
- Regular Colonoscopies: Surveillance with regular colonoscopies is typically recommended to detect and remove polyps before they become cancerous.
- Prophylactic Colectomy: In some cases, especially when a large number of polyps are present, a prophylactic colectomy (surgical removal of the colon) may be recommended to reduce the risk of colorectal cancer.
- Genetic Counseling: Individuals with FAP and their families may benefit from genetic counseling to understand the inheritance pattern, assess cancer risks, and explore options for family planning.
- Medications: Some medications may be used to reduce the number and size of polyps in certain cases.
FAP is a lifelong condition that requires ongoing medical management. Genetic testing and counseling are important components of FAP care, helping individuals and their families make informed decisions about surveillance, treatment, and prevention strategies. Early intervention and close monitoring can significantly improve outcomes for individuals with Familial Adenomatous Polyposis.
The classic form of the disease is caused by mutations in the APC gene, which codes for a tumor suppressor gene. In these cases, the disease is inherited with an autosomal dominant inheritance pattern, i.e., a single pathogenic copy is sufficient to develop the disease. The deletion c.3922_3926AAAGA (p.Glu1309fs) is the most frequent mutation causing FAP. It alters the APC gene's reading pattern, leading to the appearance of an early stop codon. Consequently, a truncated, non-functional protein is produced. It is common in Japanese, Chinese, Iranian, and South African populations.
Another FAP-related gene is MUTYH, which codes for the enzyme MYH glycosylase, which is involved in DNA repair. Two pathology-causing mutations, responsible for 80% of cases of MUTYH-associated FAP, c. 536A>G (p.Tyr176Cys) and c.1187G>A (p.Gly393Asp), stand out. These mutations have been observed in patients in both compound heterozygosis and homozygosis. Functional assays have shown that the glycosylation capacity of the enzyme is reduced to less than 4% of the usual capacity. Several studies have shown that two copies of the c.536A>G variant markedly increase the likelihood of developing CRC compared with other patients with two copies of a different variant, c.1187G>A.
The genetic test of Familial Adenomatous Polyposis (FAP) analyzes the 91 most frequent pathogenic mutations of the APC gene plus the 30 most frequent pathogenic mutations of the MUTYH gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as e.g. next-generation sequencing (NGS).
