FAP and AFAP testing: Genetic colon cancer

A small proportion of colon and rectal cancers arise in individuals who have genetic mutations. Familial Adenomatous Polyposis(FAP) and AFAP are autosomal dominant disorders with 50% risk of inheritance and about 75–80% of individuals with these conditions have an affected parent. Autosomal dominant inheritance means that an offspring of an affected individual has a 50% risk of inheriting the altered APC gene.
Adenomas develop in approximately half of all patients with FAP by age 15, and in 95% by age 35. Without intervention, most individuals with FAP will develop colon or rectal cancer by the fourth decade of life. Thus, screening and intervention for at-risk persons is critical and typically begins at puberty (National Comprehensive Cancer Network® [NCCN®], 2012). AFAP is an attenuated variety of FAP. Evidence in the published, peer-reviewed scientific literature indicates that genetic testing for mutations in the APC gene is appropriate for a specific subset of individuals who have been identified as at high-risk for FAP or AFAP. Among the specialty organizations that have recognized the role of FAP and AFAP genetic testing are the American Gastroenterological Association (AGA), American College of Medical Genetics (ACMG), NCCN and National Cancer Institute (NCI). It is generally accepted that genetic testing for FAP and AFAP is appropriate for the following purposes:
• to confirm the diagnosis of FAP and AFAP in an affected patient
• to provide predictive testing for at-risk relatives of AFAP and FAP-affected patients with known APC gene mutation.
MYH-Associated Polyposis (MAP), also known as MUTYH-associated polyposis, is a recently described syndrome that is related to FAP and that is also characterized by adenomatous polyps. It is, however, an autosomal-recessive syndrome, in which half of the affected individuals are carriers of the disease but are not affected, unless they receive one gene from each parent.

American College of Medical Genetics (ACMG) and the American Society of Human Genetics (ASHG) and American Gastroenterological Association (AGA) also offer guidelines. For genetic counseling and testing for adenomatous polyposis syndromes, including FAP, and AFAP, the guidelines include the following (NCCN, 2012):
• FAP Inclusion criteria include:
Presence of over 100 polyps, or fewer polyps at younger ages, especially in family known to have FAP
Autosomal dominant inheritance
Possible associated additional findings, including:
o Congenital hypertrophy of retinal pigment epithelium (CHRPE)
o Osteomas, supernumerary teeth, odontomas
o Desmoids, epidermoid cysts
o Duodenal and other small bowel adenomas
o Gastric fundic(body) gland polyps
increased risk of medulobastoma, papillary carcinoma of the thyroid (<2%) or hepatobalstoma (usually ?age 5 years)
Pancreatic cancers (<1%)
Gastric cancers (<1%)
• AFAP inclusion criteria include:
Fewer than 100 adenomas (range 0 – >1000) (average of 30 polyps)
Frequent right-sided distribution of polyps
Adenomas and cancers at age older than classic FAP (i.e., mean cancer age greater than 50)
Upper GI findings and thyroid cancer risk is similar to classic FAP
?Other extraintestinal manifestations, including CHRPE and desmoids are rare
• If personal history is positive, then refer to genetic screening
• If family mutation is known, then refer at-risk family members to genetic screening
For genetic counseling and testing for MAP, the guidelines include the following (NCCN, 2012):
• MAP inclusion criteria include:

  •   Polyposis or colon cancers consistent with autosomal recessive (i.e., parents unaffected, siblings affected)
  • Fewer than 100 adenomas (range 0–100s and uncommonly >1000)
  • Adenomas and colorectal cancer at age older than classical FAP (median age >50)
  • Duodenal adenomas are uncommon
  • Attenuated polyposis with negative APC gene mutation

• If personal history is positive, then refer to genetic screening
• Testing for APC gene mutations usually precedes testing for MYH mutations, except in families in which only siblings are affected
• Recommend genetic counseling and testing for germ line MYH mutations for siblings of affected patients
• If family mutation is known, then refer at-risk family members to genetic screening

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