Inactivation of germline mutant APC alleles by attenuated somatic mutations: a molecular genetic mechanism for attenuated familial adenomatous polyposis

Am J Hum Genet. 2000 Sep;67(3):582-90. doi: 10.1086/303058. Epub 2000 Aug 3.


Germline mutations of the adenomatous polyposis coli (APC) tumor-suppressor gene result in familial adenomatous polyposis (FAP). Patients with FAP typically develop hundreds to thousands of benign colorectal tumors and early-onset colorectal cancer. A subset of germline APC mutations results in an attenuated FAP (AFAP) phenotype, in which patients develop fewer tumors and develop them at an older age. Although a genotype-phenotype correlation between the locations of APC germline mutations and the development of AFAP has been well documented, the mechanism for AFAP has not been well defined. We investigated the mechanism for AFAP in patients carrying a mutant APC allele (APC(AS9)) that has a mutation in the alternatively spliced region of exon 9. APC(AS9) was found to down-regulate beta-catenin-regulated transcription, the major tumor-suppressor function of APC, as did the wild-type APC. Mutation analysis showed that both APC(AS9) and the wild-type APC alleles were somatically mutated in most colorectal tumors from these patients. Functional analysis showed that 4666insA, a common somatic mutation in APC(AS9) in these tumors, did not inactivate the wild-type APC. Our results indicate that carriers of APC(AS9) develop fewer colorectal tumors than do typical patients with FAP because somatic inactivation of both APC alleles is necessary for colorectal tumorigenesis. However, these patients develop colorectal tumors more frequently than does the general population because APC(AS9) is inactivated by mutations that do not inactivate the wild-type APC.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenomatous Polyposis Coli / genetics*
  • Adenomatous Polyposis Coli / metabolism
  • Adenomatous Polyposis Coli / pathology
  • Adolescent
  • Alleles*
  • Codon / genetics
  • Cytoskeletal Proteins / metabolism
  • DNA Mutational Analysis
  • Exons / genetics
  • Gene Expression Regulation, Neoplastic
  • Genes, APC / genetics*
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Germ-Line Mutation / genetics*
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Suppression, Genetic / genetics*
  • Trans-Activators*
  • beta Catenin


  • CTNNB1 protein, human
  • Codon
  • Cytoskeletal Proteins
  • RNA, Messenger
  • Trans-Activators
  • beta Catenin