Familial Adenomatous Polyposis

Familial adenomatous polyposis is a colorectal cancer predisposition syndrome characterized by hundreds to thousands of adenomatous polyps in the gastrointestinal tract. 

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Familial adenomatous polyposis is a colorectal cancer predisposition syndrome characterized by hundreds to thousands of adenomatous polyps in the gastrointestinal tract. 

Disease Name 
Familial Adenomatous Polyposis (FAP)
Gardner Syndrome
Turcot Syndrome
Attenuated FAP (AFAP)
Disease Information 

Familial adenomatous polyposis (FAP) is an autosomal dominant colorectal cancer predisposition syndrome caused by mutations in the APC gene and characterized by hundreds to thousands of adenomatous polyps in the colon and rectum. It affects 1/8,000 to 1/10,000 individuals and accounts for about 1% of all colorectal cancer.1 In individuals with classic FAP, colorectal polyps generally begin developing at an average age of 16 years.2 Colorectal cancer is inevitable without colectomy, and the average age of diagnosis in untreated individuals is age 35-40 years.3

Variants of FAP are Gardner syndrome, Turcot syndrome, and attenuated FAP (AFAP).1 Gardner syndrome is the association of colonic polyposis of classic FAP with osteomas and soft tissue tumors (epidermoid cysts, fibromas, desmoid tumors).4 Turcot syndrome is characterized by colonic polyposis and central nervous system (CNS) tumors, usually medulloblastoma.5 Attenuated FAP (AFAP) is characterized by fewer colonic polyps (<100 polyps), diagnosis of colorectal cancer at a later age, and a lower lifetime risk of colorectal cancer with appropriate surveillance.6 Other extra-colonic manifestations associated with FAP include polyps of the gastric fundus and duodenum, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and other cancers. Variations in phenotype may relate to the location of the mutation within the APC gene.7

Testing Benefits & Indication 

Genetic analysis of the APC gene can provide confirmation of a clinical diagnosis of FAP. Once a mutation is identified in a patient, testing of other family members can help identify carriers, including children, before clinical manifestations are present. Early identification of at-risk family members improves diagnostic certainty and reduces the need for costly screening procedures in those family members who have not inherited the disease-causing mutation.

Based on published guidelines8, APC genetic testing should be considered for any of the following:

  1. A personal history of ≥10 adenomas
  2. A personal history of adenomas and any of the following manifestations: duodenal/ampullary adenomas, desmoid tumors, papillary thyroid
    cancer, CHRPE, epidermal cysts, and/or osteomas
  3. Family history of FAP
  4. A known APC mutation in the family

APC testing can be done concurrently with MUTYH testing (see Adenomatous Polyposis) or sequentially.

Test Description 

APC coding exons 1-15 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-15. Additionally, all promoter 1B gross deletions as well as single nucleotide substitutions within the promoter 1B YY1 binding motif are analyzed and reported. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.10  Gross deletion/duplication analysis of APC using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).

Mutation Detection Rate 

Prevalence of APC mutations among those with polyposis depends on the phenotype.9 Detection rates are highest in those with classic FAP and those with a family history of polyposis (clinical sensitivity). Ambry's APC analysis can detect >99.9% of described mutations in the gene, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TECHNIQUE TURNAROUND TIME (days)
3040 APC Gene Sequence
and Deletion / Duplication Analyses                                         
                                         
14 - 21 
3042 APC Specific Site Analysis 7 - 14 
8726 Adenomatous Polyposis (APC and MUTYH Gene Sequence and
Deletion/Duplication Analyses)
14 - 21 

 

Specialty 
Genes 
APC
References 
  1. Lipton L, et al. The genetics of FAP and FAP-like syndromes. Fam Cancer. 2006. 5(3):221-226.
  2. Petersen GM, et al. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology. 1991. 100(6):1658-1664.
  3. Bisgaard ML, et al. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat. 1994. 3(2):121-125. 
  4. Gardner EJ & Richards RC. Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet. 1953. 5(2): 139-147.
  5. Hamilton SR, et al. The molecular basis of Turcot's syndrome. N Engl J Med. 1995. 332(13):839-847.
  6. Knudsen AL, et al. Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer. 2003. 2(1):43-55. 
  7. Newton KF, et al. Genotype–phenotype correlation in colorectal polyposis. Clin Genet. 2011. 81(6):521-31.
  8. Syngal S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015. 110(2):223-62.
  9. Grover S, et al. Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. JAMA. 2012. 308(5):485-492.
  10. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.