Approach Considerations
2015 ACG guidelines on genetic testing and management of hereditary gastrointestinal cancer syndromes
The American College of Gastroenterology (ACG) released the following recommendations for the management of patients with hereditary gastrointestinal cancer syndromes—and they specifically discuss genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer [14] :
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The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer.
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Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives.
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When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives.
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Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making.
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Patients who meet the clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers.
The International Society for Gastrointestinal Hereditary Tumors (InSIGHT) has proposed a staging system and stage-specific interventions for FAP. [15]
Imaging Studies
Flexible sigmoidoscopy: Visualization of more than 100 polyps usually establishes the diagnosis because of the diffuse nature of the polyposis.
Colonoscopy is usually reserved for patients thought to have AAPC because of the higher incidence of right-sided polyps (proximal colonic involvement).
Front- and side-viewing esophagogastroduodenoscopy is recommended if sigmoidoscopy or colonoscopy establishes the diagnosis of FAP. It is an essential component of the surveillance program in FAP, especially in that the second most common cancer involves the duodenum. This test helps to evaluate the presence of gastric, duodenal, and periampullary adenomas. It is recommended every 1-3 years. Benign gastric polyps are part of the spectrum of FAP. They are usually confined to the fundus.
Dental and skull x-ray films are recommended in patients thought to have a Gardner variant of FAP. The films help to detect osteomas and dental abnormalities.
Barium studies may be performed to visualize intestinal polyposis.
Periodic ultrasounds or abdominal computed tomography scans are used to check for intra-abdominal desmoid tumors and pancreatic cancer.
Periodic ultrasound of the thyroid: This imaging study is considered because of the increased risk of thyroid cancer. It can supplement the recommended annual physical examination of the thyroid.
Laboratory Studies
Laboratory tests include the following:
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Complete blood cell (CBC) count
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Alpha-fetoprotein (AFP) blood test - For children with FAP until age 5 years as part of a screening program for hepatoblastoma
Genetic testing
Three genetic tests are available. [13] Patients should receive genetic counseling from a trained individual prior to the performance of these tests.
In vitro protein synthesis assay
This is the genetic test of choice for the proband patient (patient with FAP). This test is commercially available. DNA from peripheral blood is analyzed for a truncated APC gene product.
Because of the size of the APC protein, it is analyzed in five overlapping segments. If the proband has a mutation, other family members can be tested (after genetic counseling) for the identical mutation. The test generally has 100% accuracy in detecting other gene carriers in the family.
Gene sequencing
APC gene sequencing is the most accurate test. However, it is hard logistically and, hence, is only reserved for research purposes.
Linkage testing
DNA markers near or in the APC locus are used to identify mutant gene carriers. This test requires two affected family members to achieve an appropriate linkage relationship resulting in 90% accuracy. As a result, this is not appropriate logistically
Genetic testing for a germline mutation in the APC gene should be considered in individuals with 10-20 adenomas in their lifetime, furthermore in patients with a strong family history of polyposis; larger numbers of adenomas is associated with a greater likelihood of FAP. [8, 16, 17, 18]
Counseling and screening of first-degree relatives
Offer genetic counseling before any genetic testing is performed. The patients and their family members should be made aware of the limitations of genetic testing and the associated consequences. Genetic counseling should be performed by someone familiar with FAP and the genetic tests available.
A few patients with clinical FAP have a genetic mutation that cannot be identified, and their first-degree relatives cannot be screened genetically and will require life-time clinical screenings. [19]
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Colectomy specimen obtained from a patient with familial adenomatous polyposis. Note the presence of numerous synchronous adenomatous polyps lining the luminal surface.
