Familial adenomatous polyposis (FAP), a dominantly inherited disease, is characterized by the development of multiple colorectal polyps and may progress to colorectal cancer. FAP is primarily caused by functional mutations in the adenomatous polyposis coli (APC) gene.
The APC gene product functions as a tumor suppressor, and although most mutations in it leading to cancer appear to be somatic, there are some that are inherited. Although the percent of colorectal cancer caused by mutations of the APC gene leading to the development of FAP is under 1% , germline (inherited) APC mutations are highly causative. Most mutations are in exon 15 and are either nonsense or frameshift mutations. Codons 1061 and 1309 are the most common inherited mutation sites, often resulting in a frameshift.
At least three APC mutations are relatively well known:
- The first is rs1801155, the "p.I1307K" variant found in Ashkenazi Jews, associated with a several-fold increased risk for development of multiple adenomas and colorectal cancer.
- The second is rs1801166, also known as "p.E1317Q".
- And the third is rs587782557, which leads to an attentuated form of FAP. This mutation, also known as c.426_427delAT, is linked to a founding couple who came to America from England around 1630, and who are likely to have many descendants in the US, including several Mormon kindreds among in Utah.[PMID 18063416]