APC Gene Sequencing and Deletion/Duplication Analysis for Familial Adenomatous Polyposis (FAP) and FAP-Like Syndromes

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Gene: APC at 5q21-q22 

Methodology: Bi-directional DNA sequencing of 16 exons and splice sites and/or deletion/duplication analysis by MLPA of the APC gene. 

Clinical Sensitivity: 95% for patients with a clinical diagnosis of FAP with have an APC mutation. Approximately 90% of mutations will be detected by sequencing and 8-12% by deletion/duplication analysis.

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Background

Colorectal cancer is the second leading cause of cancer death. FAP is an autosomal dominant inherited disease that predisposes patients to colorectal cancer. FAP affects approximately 1 in 8000 people accounting for approximately 0.5% of all colorectal cancers. The hallmark of classical FAP is the development of hundreds to thousands of precancerous colonic polyps, beginning at a mean age of 16 years. By age 35 years, 95% of individuals with FAP have polyps. Colon cancer is the inevitable consequence if the colon is not removed. A clinical diagnosis of FAP is made if an individual has more than 100 colorectal adenomatous polyps or less then 100 colorectal adenomatous polyps and a family history of FAP.

FAP has a broad spectrum of clinical manifestations. In addition to classical FAP, three FAP-like syndromes are recognized: Attenuated FAP (AFAP), Gardner syndrome, and Turcot syndrome. Attenuated FAP is characterized by the presence of less than 100 (average 30) adenomatous polyps, found more proximally in the colon, but still has a very high risk of developing colorectal cancer. The average diagnosis of colon cancer in individuals with AFAP is 50 to 55 years. Gardner syndrome is a variant of FAP, which is characterized by the association of colonic adenomatous polyposis, benign osteomas of the mandible and long bones, and soft tissue tumors (epidermal skin cysts, fibromas, desmoid tumors). Turcot syndrome refers to the association of colorectal polyps and cerebellar medullablastoma.

Extracolonic manifestations of classical FAP include upper gastrointestinal tumors, osteomas, dental abnormalities, congenital hypertrophy of retinal pigment epithelium at birth (CHRPE), hepatoblastoma, thyroid cancer and soft tissue tumors. About 75% of individuals diagnosed with FAP have inherited the disorder from a family member and 25% of cases are caused by new (de novo) mutations. Germline mutations in the tumor-suppressor gene, APC, are associated with this disease. Almost all individuals who carry an APC mutation will develop FAP, although there is both intra- and interfamilial variation in phenotypic expression of the disease. The majority (95%) of APC mutations are nonsense or frameshift mutations which result in a truncated protein or single or multi-exon deletions.

The American Society of Clinical Oncology and others recommend that genetic testing be part of the standard management for family members at risk for FAP. In addition to confirming the diagnosis of FAP, genetic testing allows for early identification and diagnosis of individuals at greatest risk for developing colorectal cancer, prior to the expression of typical clinical manifestations. The identification of a specific mutation can significantly impact the clinical management of these patients and facilitates the screening of their family members. Predictive testing for APC mutations may be offered to unaffected, but at-risk, family members of FAP patients. If an at-risk individual is shown not to carry the familial mutation (genotype negative), they can be definitively diagnosed as unaffected with FAP and reassured that neither they nor their offspring will be at higher risk compared to the general population to develop this disorder. The need for serial follow up by colonoscopy is also obviated. However, if an at-risk family member is found to carry the mutation (genotype positive), then they can receive appropriate and early intervention and treatment.

Synonyms (OMIM#175100):
  • FAMILIAL ADENOMATOUS POLYPOSIS; FAP
  • FAMILIAL POLYPOSIS OF THE COLON; FPC
  • POLYPOSIS, ADENOMATOUS INTESTINAL
  • GARDNER SYNDROME; GS
  • TURCOT SYNDROME; TS
  • ADENOMATOUS POLYPOSIS COLI, ATTENUATED; AAPC
  • DELETED IN POLYPOSIS 2.5

Syndromes related to FAP and also occurring due to mutations in APC include: Attenuated FAP (OMIM#175100), Gardner syndrome (OMIM#175100), Turcot syndrome (OMIM#175100).

Gene

Protein OMIM# Locus
APC Adenomatous polyposis coli 175100

5q21-q22

 

Clinical Features (variable, and may not occur in every patient)

FAP:
  • Adenomatous colonic polyps (100-1000) in childhood to adolescence
  • 95% of individuals have polyps (by age 35 years)
Extracolonic manifestations:
  • Gastric and duodenal polyps
  • Osteomas
  • Dental anomalies
  • Congenital hypertrophy of the retinal pigment epithelium (CHRPE)
  • Desmoid tumors
  • Thyroid cancer (non-medullary)
  • Epidermoid cysts
  • Other sites: liver, adrenal glands, bile duct, pancreas
Attenuated FAP (AFAP)
  • Fewer colonic polyps (average of 30) than in FAP
  • More proximally located polyps
  • Later age of onset than classic FAP (50 years)
Gardner Syndrome:
Turcot syndrome:
  • Adenomatous colonic polyposis
  • CNS tumors, usually medulloblastoma
  • Other: Stomach cancer, basal cell carcinomas
Inheritance Pattern: Autosomal dominant
  • The presence of a pathogenic mutation in one copy of the APC gene is sufficient to cause FAP, AFAP, Gardner syndrome or Turcot syndrome.
  • Children of an affected individual with an identified pathogenic mutation have a 50% (or 1 in 2) chance of inheriting the same mutation.
  • Penetrance is complete but expressivity can be variable.
  • About 75-80% of cases are inherited and 20-25% are due to a new mutation.
Test Indications:
  • Individuals with clinical features of FAP, AFAP, Gardner or Turcot syndrome.
  • Predictive testing for at-risk family members (parents, siblings, and children) of an individual diagnosed with FAP and an identified APC mutation.
Test Outcomes:
  • The detection of a pathogenic mutation in one copy of the APC gene is considered a positive test result. A positive test result confirms a diagnosis of FAP or FAP-like syndrome in a symptomatic individual. If a familial mutation is known, a positive test result confirms the presence of the mutation in an asymptomatic family member.
  • Knowledge of a specific mutation may provide information about age of onset, certain clinical characteristics, and disease severity in symptomatic individuals.
  • A negative test result does not rule out the possibility that the individual has a genetic cause of FAP. There is a greater chance that a mutation will be detected in an individual that meets the clinical criteria for FAP. Large deletions and gene rearrangements of the gene, regulatory mutations, and/or mutations in other genes could be responsible for the individual's clinical features.

Methodology

Bi-directional sequence analysis is performed on 16 exons and splice sites of the APC gene. Gross deletions and duplications of the APC gene are detected by Multiplex Ligation-dependent Probe Amplification (MLPA).

Analytical and Clinical Sensitivity

The gene sequencing assay is greater than 99.9% accurate in detecting mutations in the sequence analyzed. MLPA is 98% accurate in detecting deletions and/or duplications at the analyzed locus. According to current literature, up to 90% of APC mutations can be detected by sequencing and 8-12% by deletion/duplication analysis. The overall detection rate of mutations in the APC gene by screening patients with a clinical diagnosis of FAP is 95%.

References

Gene Reviews for APC-Associated Polyposis Conditions: http://www.ncbi.nlm.nih.gov/sites/GeneTests/
Galiatsatos P, Foulkes WD (2006). Familial adenomatous polyposis. Am J Gastroenterol: Feb;101(2):385-98.

Lipton L, Tomlinson I (2007). The genetics of FAP and FAP-like syndromes. Familial Cancer: 5(3):221-6.

Rozen P, Macrae F (2006). Familial adenomatous polyposis: The practical applications of clinical and molecular screening. Familial Cancer: 5(3):227-35.


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