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

被引:46
作者
Su, LK
Barnes, CJ
Yao, WZ
Qi, Y
Lynch, PM
Steinbach, G
机构
[1] Univ Texas, MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA
[2] Univ Texas, MD Anderson Canc Ctr, Dept Gastrointestinal Oncol & Digest Dis, Houston, TX 77030 USA
[3] Univ Texas, MD Anderson Canc Ctr, Div Canc Prevent, Houston, TX 77030 USA
关键词
D O I
10.1086/303058
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 wildtype 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.
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页码:582 / 590
页数:9
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