Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Colon Cancer Genes
Table 2. Major Genes Associated with Risk of Colorectal Cancer continued...
Adenomatous Polyposis Coli (APC)
The APC gene on chromosome 5q21 encodes a 2,843-amino acid protein that is important in cell adhesion and signal transduction; beta-catenin is its major downstream target. APC is a tumor suppressor gene, and the loss of APC is among the earliest events in the chromosomal instability colorectal tumor pathway. The important role of APC in predisposition to colorectal tumors is supported by the association of APC germline mutations with FAP and attenuated FAP (AFAP). Both conditions can be diagnosed genetically by testing for germline mutations in the APC gene in DNA from peripheral blood leukocytes. Most FAP pedigrees have APC alterations that produce truncating mutations, primarily in the first half of the gene.[6,7] AFAP is associated with truncating mutations primarily in the 5' and 3' ends of the gene and possibly missense mutations elsewhere.[8,9,10,11]
More than 300 different disease-associated mutations of the APC gene have been reported. The vast majority of these changes are insertions, deletions, and nonsense mutations that lead to frameshifts and/or premature stop codons in the resulting transcript of the gene. The most common APC mutation (10% of FAP patients) is a deletion of AAAAG in codon 1309; no other mutations appear to predominate. Mutations that reduce rather than eliminate production of the APC protein may also lead to FAP.
Most APC mutations that occur between codon 169 and codon 1393 result in the classic FAP phenotype.[8,9,10] There has been much interest in correlating the location of the mutation within the gene with the clinical phenotype, including the distribution of extracolonic tumors, polyposis severity, and congenital hypertrophy of the retinal pigment epithelium. The most consistent observations are that attenuated polyposis and the less classic forms of FAP are associated with mutations that occur in or before exon 4 and in the latter two-thirds of exon 15, and that retinal lesions are rarely associated with mutations that occur before exon 9.[10,13] Exon 9 mutations have also been associated with attenuated polyposis. Additionally, individuals with exon 9 mutations tend not to have duodenal adenomas.
Mut Y Homolog
The Mut Y homolog gene, which is also known as MUTYH and MYH, is located on chromosome 1p34.3-32.1. The protein encoded by MYH is a base excision repair glycosylase. It repairs one of the most common forms of oxidative damage. Over 100 unique sequence variants of MYH have been reported (Leiden Open Variation Database). A founder mutation with ethnic differentiation is assumed for MYH mutations. In Caucasian populations, two major variants (Y165C and/or G382D) account for 70% of biallelic mutations in MYH-associated polyposis patients, and 90% of these patients carry at least one of these mutations. Biallelic MYH mutations are associated with a 93-fold excess risk of CRC with near complete penetrance by age 60 years.