Familial adenomatous polyposis (FAP) is a rare inherited autosomal dominant syndrome characterized by the development of tens to thousands of adenomas (glandular benign tumors) in the rectum and colon, known as colorectal adenomatous polyps (1). In contrast to hyperplastic polyps which possess no malignant potential, adenomatous polyps are considered pre-malignant. Hence, FAP will inevitably progress to cancer unless treated with prophylactic surgery (2). It is estimated that one in every 8,300 individuals are affected, accounting for less than 1% of colorectal cancers (1). Classic FAP is a result of a germline mutation in the adenomatous polyposis (APC) gene; 70% of patients will have a family history of colorectal polyps and cancer whereas 30% of patients will develop FAP from a spontaneous mutation (2). FAP will affect both sexes equally, and mutations in the APC gene are nearly 100% penetrant for colonic polyposis and colon cancer (3, 7).
FAP is a member of APC-associated polyposis conditions, which include Gardner syndrome, Turcot syndrome and attenuated FAP (AFAP) (7). Although their phenotypes often overlap, FAP is distinguishable by: 1) the presence of 100 or more colorectal adenomatous polyps or 2) less than 100 polyps, in conjunction with a positive family history in individuals under forty years and a susceptibility to soft tissue and other tumors (7). On the other hand, AFAP is characterized by fewer colonic polyps, usually less than 100 at the time of presentation, and an increased risk for colon cancer; however, the criteria for identifying AFAP remains debatable (3, 7). In addition to the development of adenomatous polyps, patients with FAP may also exhibit benign extracolonic manifestations, osteomas, dental abnormalities, desmoid tumours, and congenital hypertrophy of the retinal pigment epithelium (CHRPE) (1). Today, very few cases of FAP are presented as a colonic or extracolonic malignancy (1).
The majority of classical FAP patients will have polyps developing in the distal colon during early childhood as small intramucosol nodules; by adolescence, the polyps will increase in size and number, becoming easily identifiable (1). Patients will have few symptoms during childhood - half of FAP patients will develop adenomas by the time they are 15 and 95% of patients will have developed adenomas at 35 years of age (1). The age of patients who develop colorectal carcinomas as a result of FAP ranges from 34.5 to 43 years (3).
FAP can also lead to a number of gastrointestinal and extra-intestinal manifestations. Gastrointestinal manifestations include fundic gland polyps (FGP). Sporadic FGPs will often develop in individuals without FAP, but FAP patients have pathologically distinct FGPs with adenomatous features (1). These FGPs will rarely progress to cancer. Adenomatous polyps in the duodenum and periampulary region will also develop in 90% of individuals with FAP (1). These polyps generally develop a decade or two following diagnosis of colorectal polyps, and 5% of these polyps will progress to cancer within 10 years (1). Adenomas can also develop in the small bowel. These carry a smaller risk of cancer progression than duodenum and ampulary polyps (1). A relative risk for pacnreatic and thyroid cancers has also been observed in FAP (7). Extra-intestinal manifestations may include the presence of osteomas, congenital hypertrophy of the retinal pigment epithelium (CHRPE), epidermoid cysts and desmoid tumors (7). Osteomas are benign lesions that develop characteristically in the jaw; osteomas due to FAP will lead to dental abnormalities (1). CHRPE results in pigmented ocular fundus lesions, CHRPE causes no symptoms but can be used as a marker for families affected by FAP (3). Patients with FAP are 800 times more at risk for developing desmoid tumors (8).
The APC gene
The adenomatous polyposis (APC) gene is a tumour suppressor gene found on the long arm of chromosome 5 in band q21 (1). The gene produces a cytoplasmid protein that binds and regulates the degradation of β-catenin (4). APC plays a role in Wnt signalling, which regulates the stability of a protein complex containing β-catenin, conductin, and glycogen synthase kinase 3 (1). β-catenin is responsible for the anchorage of the actin cytoskeleton and may transmit contact inhibition, causing cells to stop dividing (5). β-catenin also targets c-myc, a commonly targeted proto-oncogene that regulates transcription of critical cell-proliferation genes (1). Mutations in the APC gene will result in loss of APC function, increasing the amount of β-catenin, therefore increasing Myc expression.
Genetic Screening and FAP Diagnosis
There have been over 700 different disease causing APC mutations, most of which involve the truncation of the APC protein by introduction of a premature stop codon (6). Screening for FAP was previously performed using protein truncation testing (PTT), but these tests would miss more than 10% of APC mutation carriers (6). Newer testing methods for FAP use DNA sequencing; even though there are more cost effective ways for mutation detection, sequencing remains the gold standard for mutation detection (1). In some cases mutations in the human MutY homologue (MUTYH) gene can also lead to polyposis and colorectal adenomas (6). These individuals are often homozygous or compound heterozygous carriers of the MUTYH mutation (6). Unlike mutations in APC, however, MUTYH mutations are inherited in an autosomal recessive manner; MUTYH-associated polyposis (MAP) share a similar phentoype to FAP (7).
FAP diagnosis is done based on a combination of family history and clinical findings, diagnoses will be confirmed by genetic testing when possible (1). More than often clinical diagnosis will be dependent on the physician. Patients will often have very few symptoms, although rectal bleeding and abdominal pains are common depending on the stage of polyp development (1). Finding a detailed family history and performing a sigmoidoscopy or full colonoscopy help to identify FAP, especially in older patients (1). Prior to genetic testing patients diagnosed with FAP must be referred to a genetic counsellor (1). While the patient could have a de novo APC mutation or an inherited MUTYH mutation on both chromosome copies, approximately 70% of FAP patients carry a germline APC mutation (1). This has implications for the patients family members as one of the probands parents must have been a carrier indicating a risk for all blood relatives. It may also affect decisions regarding child bearing as the mutation carriers offspring will have a 50% chance of inheritance(1).
Treatment and Management of FAP Patients
Treatment and management of FAP aim to maintain a high quality of life and lower the cancer risk of patients. Large bowel endoscopies are performed frequently on FAP patients, after genetic diagnosis and baseline sigmoidoscopy; younger patients are followed annually with colonoscopic examinations (1). Due to the systemic effects of FAP mentioned earlier, other examinations are suggested to track the progression of the disease. At around an age of 20 years, prophylactic cancer-preventive colorectal surgery is performed to remove the polyps. Choices of surgery include: subtotal colectomy with ileorectal anastomosis (IRA), total proctocolectomy with ileostomy, proctocolectomy with or without mucosectomy and ileal pouch anal anastomosis (IPAA) (1). Complication rates between IRA and IPAA are similar but cancer development following IPAA is significantly lower than IRA (6). Most institutions now advocate total proctocolectomy with IPAA reconstruction for FAP patients. The initial follow-up will involve CT or MRI detection for tumours. Annual surveillance of the reconstructed pouch is essential following IPAA (1).
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5. Zhou, Lu, Ercolano, Emanuela, Ammoun, Sylwia, Schmid, M. Caroline, Barczyk, Magdelena A, Hanemann, Clemens Oliver. (2011). Merlin-Deficient Human Tumors Show Loss of Contact Inhibition and Activation of Wnt/β-Catenin Signaling Linked to the PDGFR/Src and Rac/PAK Pathways.Neoplasia 13, 1101-1112.
6. Galiatsatos, Polymnia and Foulkes, William D. (2006). Familial Adenomatous Polyposis. The American Journal of Gastroenterology 101, 385-395.
7. Jasperson KW, Burt RW. APC-Associated Polyposis Conditions. 1998 Dec 18 [Updated 2011 Oct 27]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1345/
8. Nieuwenhuis, M.H., et al. (2011). A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses. Int J Cancer 129, 256–61.