Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC

Abstract
Approximately 130,000 cases of col ore eta I cancer (CRC) are diagnosed in the United States each year1, and about 15% of these have a hereditary component2,3. Two well-defined syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), account for up to 5% of the total new cases of CRC4. Truncating APC mutations are responsible for FAR5,6, and defective mismatch repair genes cause HNPCC4,7,8. However, the genes responsible for most of the familial cases are unknown. Here we report a mutation (T to A at APC nucleotide 3920) found in 6% of Ashkenazi Jews and about 28% of Ashkenazim with a family history of CRC. Rather than altering the function of the encoded protein, this mutation creates a small hypermutable region of the gene, indirectly causing cancer predisposition.