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Inactivation of Germline Mutant APC Alleles by Attenuated Somatic Mutations: A Molecular Genetic Mechanism for Attenuated Familial Adenomatous Polyposis
Ist Teil von
American journal of human genetics, 2000-09, Vol.67 (3), p.582-590
Ort / Verlag
Chicago, IL: Elsevier Inc
Erscheinungsjahr
2000
Quelle
Free E-Journal (出版社公開部分のみ)
Beschreibungen/Notizen
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 β-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.