Familial polyposis: recent advances

Abstract

Familial adenomatous polyposis (FAP) is a dominantly inherited disease characterized by the development of numerous adenomatous polyps and a high risk of colorectal cancer. Affected individuals have multiple adenomas at various intermediate stages between benign and malignant, so FAP is a supportive model for the adenoma-carcinoma sequence of colorectal carcinogenesis. The APC (adenomatous polyposis coli) gene, which is a tumor suppressor gene, was discovered in 1991, and mutation of this gene was found to be the cause of FAP. To date, more than 150 germ-line mutations have been determined in FAP patients, and more than 300 somatic mutations of the APC gene have been detected in colorectal adenomas and carcinomas from both FAP and non-FAP patients - almost all of these resulting in truncated APC protein. The nature of germline and somatic mutations is described in detail herein, including the finding of several codons in which no germ-line, but only somatic mutation, frequently occurs. Existence of somatic APC mutations in adenomas from both FAP and non-FAP patients suggests that inactivation of the APC gene by two mutations is generally involved in the development of adenoma. Further development of adenoma to advanced carcinoma is associated with loss of heterozygosity (LOH) of the APC gene and additional inactivation of multiple tumor suppressor genes (possibly through mutation and LOH) that include the p53 gene, DCC gene and tumor suppresor genes on chromosomes 1p, 8p and 22q in both FAP and non-FAP patients. Recent findings on the correlation of these genetic changes with the adenomacarcinoma sequence are also described. In vitro models for carcinogenesis, and experiments of suppression of tumorigenicity in advanced colon carcinoma cells by introduction of a normal single chromosome or a normal suppressor gene are also referred to. Furthermore, evidence of inactivation of the APC gene in extracolonic tumors, in FAP patients, including desmoid and adrenocortical tumors, is demonstrated. This confirms the pleiotropic effect of the mutant APC gene on both colonic and extracolonic manifestations in FAP patients, and that the normal APC gene acts as a growth control gene throughout the body