Molecular and clinical study of familial adenomatous polyposis for genetictesting and management

Familial adenomatous polyposis (FAP) is an inherited predisposition to colo rectal cancer characterized by the development of numerous adenomatous poly ps, predominantly in the colorectal region. Germline mutations of the adeno matous polyposis coli (APC) gene are responsible for familial adenomatous p olyposis. We examined germline mutations of the APC gene and clinical featu res among eighty-seven individuals who consisted of thirty-nine FAP-patient s, thirty-seven of their family members with a 1 in 2 risk of predispositio n to this disease, and eleven normal persons. We accurately identified nine heterozygotes, among individuals with a 1 in 2 risk by genetic testing, wi thout the uncertainty of the recurrence risk calculated by Bayes' theorem. Six of the nine heterozygotes were confirmed to have colorectal polyps by c olonoscopic examination. Since they were diagnosed at 12.7 years-of-age on average, and were no more than 20 years old, they could be treated to preve nt colorectal cancer. Based on the genotype-phenotype correlation, we concl uded that the germline mutations responsible for the sparse polyps phenotyp e of FAP-patients tend to locate from codon 1055 in the proximal region of the APC gene, while those for the profuse type locate from codon 1102 in th e distal region. Among the thirty-nine FAP-patients, we found that those wi th the germline mutations within codon 1055 and codon 1262 had colorectal c arcinomas of an advanced stage, at a high rate (71.4%), Special attention a nd aggressive intervention is needed in these patients and relatives at ris k. With reasonable and appropriate management, it should be possible to prolon g and improve the quality of life of those family members both affected and at risk.