Genetic Analysis of an Inherited Predisposition to Colon Cancer in a Family with a Variable Number of Adenomatous Polyps

We studied a large kindred with a history of colorectal cancer of early onset. Proctosigmoidoscopic examination of 51 family members identified only 2 with familial polyposis coli, which strongly predisposes those who have it to colorectal cancer and which is defined as the presence of more than 100 polyps in the colon. However, eight family members had 2 to 40 colonic polyps. We suspected that in this family, colorectal cancer was the result of a mutation in the gene on chromosome 5 that is responsible for familial polyposis coli. To test our hypothesis, we obtained genotypic information on 81 family members with respect to seven polymorphic DNA markers previously shown to be linked to the locus for familial polyposis coli. Multilocus analysis of the data demonstrated genetic linkage (lod score, 5.58) between these markers and the locus responsible for the defined syndrome of colonic polyps or colorectal cancer in this kindred. These findings constitute evidence that the genetic defect in this family is a mutation in the gene that causes familial polyposis coli. We conclude that mutations at the genetic locus for familial polyposis coli may be the cause of other, more subtle syndromes involving an inherited susceptibility to coIonic adenomatous polyps and colorectal cancer. (N Engl J Med 1990; 322:904–8.) COLON carcinoma is the second leading cause of death due to cancer in the United States. Because genetic factors are thought to contribute substantially to the pathogenesis of about 10 percent of cases of colorectal cancer, it is important to understand these genetic components in as much detail as possible. A specific genetic condition, familial adenomatous polyposis coli, occurs in approximately 1 in 8000 persons. If it remains untreated, there is a high probability that adenocarcinoma will develop in the patient at a relatively young age. According to present evidence, the neoplasm arises from a preexisting adenomatous polyp. 1 , 2 A diagnosis . . .