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| Clinical Background: | The APC gene is a tumor suppressor gene, especially important in early colorectal carcinogenesis. The APC I1307K point mutation is found in 6% of Ashkenazi Jews, and about 28% of Ashkenazim with a family history of colorectal carcinoma (CRC). The I1307K mutation has not been found in anyone who is not of Ashkenazi descent. Other mutations of the APC gene are responsible for Familial Adenosis Polyposis (FAP) asyndromein which massive numbers of adenomatous polyps of the colon are formed, and affected patients progress to colon cancer at a very early age (<). These mutations differ from the I1307K mutation in that they cause a variety of nonsense mutations (stop codon producing) within the APC coding region, which cause premature truncation of the APC protein. These mutations render the protein non-functional. Tumors arising in such individuals contain a second hit causing inactivation of the remaining APC allele. The I1307K mutation results in an amino acid substitution, isoleucine (I) to lysine (K), which is not felt to affect protein function. Rather, this allele becomes hypermutable, specifically to frame shift mutations at the newly formed polyA site. (Frameshift mutations, if appropriately positioned in the gene, destroy protein function because of the non-sense amino acids encoded). | |||||||||||||||||||
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