Cohorts with familial disposition for colon cancers in chemoprevention trials.

Colon cancer provides an attractive setting for chemoprevention trials because of the frequency and variation of familial predisposition that is observed in this malignancy. Additionally, the adenomatous polyp, the precursor of colon cancer, is a valuable intermediate marker for judging the effectiveness of candidate chemopreventive agents. Inherited colon cancer susceptibility varies from mild to severe. Conditions with extreme susceptibility include the autosomal dominantly inherited syndromes of familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). These are highly penetrant syndromes with extreme cancer risk. FAP arises from mutations of the APC gene and HNPCC from mutations of the mismatch repair genes. Specific and individual genetic diagnosis is now possible in both syndromes, thus allowing identification of genetically affected individuals for chemoprevention trials. FAP accounts for less than 1% of colon cancers, while HNPCC may be present in up to 5% of cases. Familial clustering is common in the remainder of cases, which are often referred to as sporadic, but probably arise in part from inherited susceptibility. Epidemiologic studies have shown that first-degree relatives have a two- to four-fold increased risk of acquiring colon cancer compared to the general population. Ten percent of individuals in the U.S. have a first-degree with colon cancer. This clinically identifiable higher risk group thus constitutes a large potential cohort for chemoprevention trials. The common familial cases of colon cancer can be further stratified by severity. A relative diagnosed under the age of 50 or two first-degree relatives affected with colon cancer confers an even greater risk for this malignancy, estimated to be four to six times that of the general population. Adenomatous polyps also precede the development of colon cancer in these categories, thereby providing a readily identifiable clinical endpoint to judge the effectiveness of chemoprevention. It is expected that genetic markers will soon be available for more precise identification of common colon cancer susceptibility. Candidate markers include mild mutations of the APC and mismatch repair genes, glutathione transferase isoenzymes, acetylator status, and phospholipase A2 expression. Bile acid concentrations of the bowel may be genetically and/or environmentally determined and likely have a role in colon cancer susceptibility. We recently identified a large kindred with polyp and cancer susceptibility arising from a mild mutation of the APC gene. There are over 4,000 kindred members and mutational testing has demonstrated 140 gene carriers to date. We expect to institute chemoprevention trials in this kindred using adenomatous polyp number as an endpoint of effectiveness.