Clinical Utility of Testing

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Genetic testing is the standard of care for management of individuals with FAP.1 Diagnostic testing establishes the FAP genotype in the family and provides the opportunity for conclusive genetic testing for at-risk asymptomatic family members. Early detection of FAP and attenuated FAP may allow for early intervention and prevention of colorectal cancer. The use of genetic testing for recognition of presymptomatic family members improves their diagnosis of FAP and circumvents costly colorectal cancer surveillance in those who have not inherited the FAP-associated mutation. Not only is genetic testing more cost effective than repeated sigmoidoscopy screening for at-risk family members, but life expectancy of individuals with FAP is extended as well. Germline mutations in the Mut Y homologue (MYH) gene also may be evaluated concurrently with APC mutations due to the overlap of phenotypes (see Interpretation of Test Results below).

Genetic testing is appropriate for presymptomatic at-risk family members of an individual diagnosed with FAP, and is ideally offered in adolescence, prior to the age when colon screening by sigmoidoscopy or colonoscopy would begin. Prenatal testing also is available for FAP. DNA extracted from fetal cells obtained by amniocentesis or chorionic villus sampling may be used for genetic testing. Requests for prenatal diagnosis of adult-onset diseases remain controversial, and provide a challenging situation that mandates careful and thoughtful genetic counseling.

APC mutations are less frequently identified in those diagnosed with FAP without a family history than in those individuals with a family history.6 Children of an affected individual have a 50% chance of inheriting their parent's mutation and should be offered genetic testing at an appropriate age. Those that test negative for an APC mutation (within the context of a known mutation in the family) remain at the general population risk for colorectal cancer and may forego colorectal cancer screening until age 50. Those testing positive will require heightened cancer surveillance and prevention at an earlier age.

Genetic testing may be offered to individuals of Ashke-nazi Jewish ancestry who have a personal or family history of colon cancer or polyps, or those that have a heightened concern for colon cancer. Genetic testing for I1307K in the Ashkenazi Jewish population has been met with some controversy, as the value of the testing may be limited if the management of individuals positive for the variant is unchanged. A good proportion of the individuals with this variant have a close relative affected with colon cancer or personal risk factors that already increase the need for col-orectal cancer screening regardless of whether the person carries the I1307K variant.

Identification of the location of the mutation in the APC gene may provide clinical insight into the management and surveillance of FAP patients. FAP manifestations may be associated with the location of the mutation within the APC gene. Mutations associated with classic FAP are found from codon 168 to codon 1600, in which the full range of phenotypes may be seen. Truncating mutations between codons 1403 and 1578 are associated with extracolonic manifestations such as desmoid tumors and osteomas, but not CHRPE.57 CHRPE-associated mutations are associated with mutations between codons 463 and 1387. A particularly severe form of FAP with several thousand colonic polyps is associated with mutations between codons 1350 and 1464. Desmoid tumors are more frequently (61%) associated with mutations between codons 1444 and 1580 than mutations prior to codon 1444.8

In attenuated FAP, mutations of the APC gene are generally identified in three distinct regions. The first region is at the 5' end of the APC gene and extends to codon 157 in exon 4. The second region consists of an alternatively spliced area of exon 9, and the third region begins at the distal 3' end of the APC gene beyond codon 1595 in exon 15.2 Attenuated FAP patients with mutations at the amino terminus demonstrate the greatest variation in the number of colorectal adenomas. In addition, a more severe pheno-type of upper gastrointestinal lesions is seen in these individuals than in those with mutations in either exon 9 or the 3' region of the APC gene. Mutations in the extreme 5' end of the APC gene may result in a nearly full-length functional protein by the initiation of translation downstream of the mutated site.9 These proteins appear to have the ability to downregulate both P-catenin and Wnt signaling, and to induce cell cycle arrest, suggesting that the amino terminus may not be required for APC function. Although genotype-phenotype correlations aid in predicting possible clinical manifestations, these correlations are not certain.

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