Molecular Basis of Disease

The identification of the APC (adenomatous polyposis coli) gene, responsible for FAP, was greatly facilitated by a patient with polyposis and an interstitial deletion of 5q visible by cytogenetic analysis. Subsequent linkage analysis confirmed the localization of the FAP gene to 5q21. Individuals affected with FAP contain one germline APC mutation and acquire an additional somatic mutation of the normal (wild-type) allele during their lifetime. Additional somatic mutations must occur before transformation occurs. Approximately one third of all FAP cases are due to de novo mutations with no family history of poly-posis or colorectal cancer.

The APC gene has several alternatively spliced forms. When translation begins at the first methionine, a 2,843

amino acid protein results. The majority (75%) of the gene is contained in a 6,579 base pair (bp) open reading frame within exon 15. The APC protein functions in cell adhesion, signal transduction, and transcriptional activation,2 and is localized to the nucleus and membrane/cytoskeleton in human epithelial cells. It binds to GSK3P, P-catenin, y-catenin, tubulin, and EB1. P-catenin functions in cell adhesion by binding to E-cadherin. The cytoplasmic level of P-catenin is suppressed by APC-mediated degradation, preventing activation of oncogenes, such as MYC and cyclin D1 by a T cell transcription factor (Wingless- Wnt signal mediator). Failure of the APC protein to maintain low levels of P-catenin results in activation of these growth-promoting genes. APC also accumulates at the kinetochore during mitosis, contributes to kinetochore-microtubule attachment, and may play a role in chromosome segregation.

An extensive number of FAP families have been examined for mutations in the APC gene. Most deleterious mutations cause loss or disruption of the central P-catenin binding region of the APC protein. Of the FAP families studied, approximately 80% have been demonstrated to contain intragenic mutations that result in the truncation of the APC protein. Truncating mutations were the result of nonsense mutations (33%), small insertions (6%), and deletions (55%), largely in the first half of exon 15.5 Several hundred mutations of the APC gene have been reported, with the two most common mutations found in codons 1061 and 1309. Individuals with mutations in codon 1309 tend to exhibit a great number of colonic adenomas at an earlier age.

A missense mutation at codon 1307 (I1307K) of APC is found in the Ashkenazi Jewish population. Individuals with the I1307K mutation have an estimated odds ratio of 1.85 or a 10% to 20% lifetime risk of developing colon cancer. This mutation results in a lysine substitution of an isoleucine and is believed to increase the risk of colorectal cancer by creating a hypermutable site. Of Ashkenazi Jewish families with a family history of colorectal cancer, 28% are estimated to have this variant. I1307K is found in approximately 6% of the Ashkenazi Jewish population but is extremely rare in the general population. This mutation does not result in the polyposis phenotype. Colorectal cancers associated with I1307K are identical to sporadic colorectal tumors.

A second missense variant in the APC gene has been described that may be associated with a predisposition to colon cancer. A consensus has not been reached regarding the role of the E1317Q mutation in colon cancer or adenomas. At this time, clinical mutation testing specific for E1317Q is not available.

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