Interpretation of Test Results

The sensitivity or accuracy of genetic tests varies by the method used. Common genetic testing methods for APC mutation detection include protein truncation, linkage analysis, sequencing, and ASOH. Protein truncation assays will detect a mutation in approximately 80% of FAP families. When used in combination with other mutation detection methods such as SSCP, the mutation detection rate may improve to 90%. In linkage analysis, the linkage of a specific haplotype with FAP in a family provides 95% to 99% accuracy in identifying carriers. The sensitivity for DNA sequencing is reported to range from 90% to 99%. The sensitivity of genetic analysis for the I1307K variant of the APC gene by ASOH or sequencing approaches 100%.

Unfortunately, not all individuals that meet the clinical criteria for FAP have an identifiable mutation. In approximately 30% of affected families, an identifiable APC mutation is not found. This may be the result of large rearrangements of the APC gene, an upstream mutation that reduces the expression of the gene, or perhaps other susceptibility loci such as MYH. Many individuals with polyposis that test negative for mutations in APC may have an autosomal recessive disorder caused by the inheritance of mutations in the MYH gene.10 For those with multiple adenomas (15 to 100), about one third will have biallelic mutations in MYH. Due to the high incidence of MYH mutations in individuals with polyposis, MYH often is evaluated in conjunction with APC genetic testing.

For classic FAP, DNA testing usually is suggested for children at 10 years of age or older, as colon surveillance is recommended to begin at 10 to 12 years of age.1 For individuals at risk for attenuated FAP, colon screening should begin at 18 to 20 years of age and so genetic testing should be offered at that time. There is some debate as to the adequacy of using flexible sigmoidoscopy or if full colonoscopy is required for surveillance. Prophylactic colectomy should be performed to prevent colon cancer after adenomas are identified, but controversy remains regarding the timing and extent of the procedure (ileorec-tal anastomosis or ileoanal pouch anastomosis). If a rectal segment remains after surgery, routine endoscopic screening is required on a biannual basis. The use of oral non-steroidal antiinflammatory Cox-2 inhibitors to prevent or eliminate polyps in the retained rectum has been reported to be effective in the short term but has not been recommended as a means of primary care.1

In addition to colorectal surveillance, patients need to be examined for extracolonic manifestations throughout their life at regular intervals, before and after surgery. Upper endoscopic screenings of the stomach, duodenum, and periampullary region is suggested every 6 months to 3 years. Cox-2 inhibitors have been reported to regress duodenal adenomas in some, but not all studies.1 Small bowel x-ray is suggested every 1 to 3 years when duodenal adenomas are detected or before colectomy. Annual examination of the thyroid is warranted and ultrasonography may be considered. Children under the age of 5 years whose parents are affected with FAP may benefit from screening of serum alpha-fetoprotein levels and imaging of the liver to detect hepatoblastoma. Detection of this rapidly growing, often fatal tumor at an early stage provides the best opportunity for cure. For families with FAP but without an identified APC mutation, members must participate in intensive, long-term colorectal cancer surveillance.

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