Familial adenomatous polyposis (FAP) is a cancer predisposition syndrome and includes a milder, attenuated form (AFAP) of the disease. Individuals with FAP develop hundreds to thousands of adenomatous polyps in their colon, sometimes beginning in childhood. Without surgical intervention, they have nearly a 100% risk of developing colorectal cancer. Untreated, the mean age of colon cancer diagnosis is 39. Individuals who have AFAP generally develop 100 or fewer polyps in their lifetime. They have a lower risk of colorectal cancer (approximately 70%) than individuals who have classic FAP.
Individuals with FAP/AFAP also have an increased risk for other cancers, including upper gastrointestinal tract tumors, pancreatic, thyroid, central nervous system, and liver (hepatoblastoma in children under age 5) cancer. Rare individuals with specificAPC genetic variants develop massive polyposis of the stomach and have an increased risk of gastric adenocarcinoma (GAPPS). Non-cancer features of FAP/AFAP include congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, epidermoid cysts, osteomas, dental abnormalities, gastric fundic gland polyps, and gastric and duodenal adenomas.
Cancer Type | FAP | General Population |
Colorectal | Approaches 100% | 4.1% |
Duodenum | Up to 10% | <1% |
Gastric | Up to 7% | 0.8% |
Thyroid, papillary | 1.2-12% | 1.2% |
Central nervous system | 1% | <1% |
Hepatoblastoma | 0.4-2.5% | <1% |
Adapted from NCCN v.1.2023
FAP is a rare condition affecting approximately 1 in 6,800 to 31,000 individuals. FAP accounts for less than 1% of colorectal cancer cases.
A pathogenic variant (mutation) that is identified by molecular genetic testing of theAPC gene.
A diagnosis of FAP is now established by molecular genetic testing. In the absence of genetic testing, a clinical diagnosis can be made if an individual has early onset of 100 or more adenomatous colon polyps.
There are no clinical diagnostic criteria for AFAP. Generally, a clinical diagnosis is suspected when an individual has between 10 and 99 adenomatous colon polyps, or more than 100 polyps diagnosed at an older age than that expected for FAP (age 35–40 or older).
FAP/AFAP is an autosomal dominant condition caused by a pathogenic variant in APC. First-degree relatives of an APC carrier have a 50% chance of also carrying the variant. Men and women are equally likely to inherit, and pass on, a pathogenic variant. Seventy percent of cases are familial or inherited and 30% of cases arede novo, or sporadic, pathogenic variants.
Clinical testing includes gene sequencing and deletion/duplication analysis of , most often using a multigene panel. Gene sequencing will identify up to 90% of individuals with FAP/AFAP, and deletion/duplication testing an additional 8-12%.
Criteria have been developed to identify individuals who would most benefit from genetic testing, based on red flags in the personal and family cancer history. Generally this includes:
Management of classic FAP and AFAP may different significantly. Management by physicians or centers with expertise in FAP and AFAP is recommended, and recommendations should be individualized based on clinical presentation and specificAPC variant, as well as other personal considerations. Management usually includes early screening and colectomy or proctocolectomy after the onset of polyposis. Screening should also include evaluation for extra-intestinal manifestations. For children under 5 years of age, screening also includes liver palpation, abdominal ultrasound, and measurement of AFP. Published guidelines with age-specific management recommendations are available (see below).
While almost all APC pathogenic variants result in AFAP/FAP, there is a common APC variant, I1307K, which only confers a moderate lifetime risk of colorectal cancer. This variant is seen in 6 - 10% of the Ashkenazi Jewish population. Colonoscopy screening in these individuals should begin at age 40, or 10 years prior to any colorectal cancer diagnosis in a first-degree relative, and repeated every 5 years if negative.
There are other hereditary cancer syndromes that increase the risk for polyps and colorectal cancer, includingMUYTH-associated polyposis (MAP), Juvenile Polyposis syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. The presentation of these syndromes in a family may overlap with that of FAP/AFAP, but can sometimes be distinguished based on characteristic features, such as physical exam findings and polyp pathology. In addition, a number of common genetic susceptibility variants are thought to increase polyp and colorectal cancer risk beyondAPC. There are likely other genes that contribute to polyp development which have not yet been identified. SeeGeneReviews for more information about the genetic differential diagnosis for FAP.
American Society of Clinical Oncology (2022): Familial Adenomatous Polyposis.
GeneReviews (2022): APC-Associated Polyposis Conditions.
Medline Plus (2020): Familial Adenomatous Polyposis.
National Cancer Institute (2023): Genetics of Colorectal Cancer PDQ – Major Genetic Syndromes.
American College of Gastroenterology (2015): Clinical Guideline on Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes.
American College of Medical Genetics & National Society of Genetic Counselors (2014):Referral Indications for Cancer Predisposition Assessment.
National Comprehensive Cancer Network (v.1.2023): Genetic/Familial High Risk Assessment: Colorectal https://www.nccn.org/(Free registration required for access).
Updated August 2023