Molecular Diagnosis of Familial Adenomatous Polyposis

Familial adenomatous polyposis is an inherited disease characterized by multiple colorectal tumors. The diagnosis has classically been based on the detection of multiple colorectal adenomas. The recent identification of germline mutations of the APC gene in patients with familial adenomatous polyposis makes presymptomatic molecular diagnosis possible, but the widespread distribution of the many mutations within this very large gene have heretofore made the search for such mutations impractical. We describe a novel approach that allows molecular genetic diagnosis in the majority of patients with the disease. We screened 62 unrelated patients from the Johns Hopkins Familial Adenomatous Polyposis Registry for germline APC mutations. Primary screening was accomplished by analysis of protein synthesized in vitro from surrogate APC genes. In addition, the relative amount of transcript from each APC allele was determined with an allele-specific-expression assay. The protein assay revealed truncated protein in 51 of the 62 patients (82 percent). In 3 of the 11 remaining patients, the allele-specific-expression assay revealed significantly reduced expression of one allele of the APC gene. The use of these two assays in combination successfully identified germline APC mutations in 87 percent of the 62 patients. The protein and allele-specific-expression assays provide a practical and sensitive method for molecular diagnosis of familial adenomatous polyposis. This approach will facilitate care, allowing routine testing of subjects at risk and genetic confirmation of spontaneous mutations., Familial adenomatous polyposis is a dominantly inherited syndrome characterized by the progressive development of hundreds of adenomatous colorectal polyps, some of which inevitably progress to cancer. Although the clinical manifestations of this syndrome and its variants (e.g., Gardner's syndrome and Turcot syndrome) have been known for many years,¹ the diagnosis still relies largely on the detection of numerous colorectal polyps during the second or third decade of life. Today, with familial adenomatous polyposis affecting nearly 1 in 8000 people² and twice that many at risk, there are more than 50,000 people in the United States alone whose families could benefit…