The two best described familial predispositions to colorectal cancer are familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC). Recent advances make genetic diagnosis of these predispositions a reality. FAP is due to germline mutations in the APC tumor suppressor gene whereas HNPCC is caused by mutations in any one of at least four human DNA mismatch repair (MMR) genes. While these findings have paved the way for genetic diagnosis of FAP and HNPCC, many critical issues must be addressed before this work can be optimally translated to a clinical setting. The studies proposed in this application have three aims. The first is improving the sensitivity of testing for FAP and HNPCC. We have previously developed assays that can identify the genetic defect in about 80% of FAP and 50% of HNPCC patients. Recently, we have developed a sensitive and novel strategy for mutational testing (MAMA) which can detect mutations missed by conventional assays. In an effort to improve, screening sensitivity, we will use MAMA to test FAP and HNPCC patients who have tested negative with conventional analyses. Second, we will determine which patient populations warrant screening for APC and MMR gene alterations. Our previous studies have largely focused on patients who meet the classic criteria for FAP and HNPCC. However, we have identified APC and MMR mutations in several patients who do not meet these criteria. We will extend these studies to other similar patient populations who may have a predisposition to colorectal cancer. Third, we will attempt to improve the accuracy of testing by using functional tests to evaluate the disease- causing potential of selected mutations. A subset of the variants identified in the APC and MMR genes result in relatively subtle changes in the encoded protein. Determining whether these changes represent disease- causing mutations or harmless variations requires functional analysis. Together, these studies should provide information necessary for the translation of genetic testing for hereditary colorectal cancer syndromes to the clinic.
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