Adenomatous Polyposis Syndromes
Familial Adenomatous Polyposis (FAP)
This syndrome is an autosomal dominant disease that accounts for less than 1% of all colorectal cancers. Affected patients, if not treated, have a colorectal cancer risk of almost 100%, at a mean age of 39.
FAP is clinically characterized by the presence of hundreds or even thousands of adenomatous colon polyps. On average, polyp appearance starts at age 16, but they can be present at a much younger age. These patients are also at higher risk for upper gastrointestinal tract tumors, desmoid tumors and thyroid cancer.
Besides the classical FAP, three variants of the syndrome have been found: Gardner syndrome, Turcot syndrome and attenuated FAP (AFAP).
Gardner syndrome is characterized by all the manifestations of FAP plus benign extracolonic tumors such as desmoid or soft-tissue tumors, osteomas and dental abnormalities.
Turcot syndrome is characterized by the development of central nervous system malignancies such as medulloblastomas, astrocytomas and ependymomas. Most patients also commonly present typical FAP features.
For information on Attenuated Familial Polyposis Syndrome (AFAP) click here.
Genetic testing and FAP
FAP is hereditary, and is caused by germ-line mutations in the Adenomatous Polyposis Coli (APC) gene, located on chromosome 5q21. One inherited mutated allele from an affected parent, and the subsequent development of an acquired (or somatic) mutation in the other APC allele results in uncontrolled cell growth and development of adenomas.
APC synthesizes a protein that is one of the main components of the Wnt signaling pathway. It forms a multi protein complex with Axin2 and b-catenin to prevent the translocation of b-catenin to the nucleus where it binds the Tcf family of transcription factors.
There is a strong correlation between genotype and phenotype in this syndrome. Most of the pathogenic mutations in this gene are located in the 5' end of exon 15, in the region called mutation cluster region (MCR). Mutations in codons 1061 and 1309 are mutational hotspots and result in a severe polyposis phenotype. These pathogenic mutations are usually translated into a stop codon insertion resulting in a non-functional truncated protein.
When a patient has clinical evidence of FAP, genetic analysis has to be performed. Since mutations are found in many different spots, analysis of the entire APC gene is necessary. However, about 30% of FAP cases arise de novo and the proband is the first person in the family to be affected, which may fatally delay diagnosis.
Different molecular techniques are used to identify mutations in this gene. As the majority of the pathogenic mutations result in a truncated protein, the protein truncation test (PTT) can be used as a prescreening test to detect alterations in this gene. Once the latest test has yielded a truncated fragment, the corresponding DNA fragment has to be sequenced to detect the disease-causing mutation.
Today, many labs no longer perform pre-screening with PTT analysis; they proceed directly to germ-line mutation analysis. This identifies up to 95% of the mutations described in the gene. In a smaller percentage of cases, this gene presents large deletions and rearrangements and mutation detection is accomplished through Southern blotting or Multiple Probe Ligation Amplification (MLPA) techniques.
If a mutation can be identified in a proband, family members can be unequivocally tested for that mutation. This allows for an appropriate management with prophylactic total colectomy (or subtotal colectomy if there is relative rectal sparing of polyps) and upper gastrointestinal tract screening for patients who have inherited the mutation. Family members who had not inherited the mutation can then be spared unnecessary procedures and anxiety.
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