Analysis of somatic APC mutations in rare extracolonic tumors of patients with familial adenomatous polyposis coli
| Autor: | Hendrik, Bläker, Christian, Sutter, Martina, Kadmon, Herwart F, Otto, Magnus, Von Knebel-Doeberitz, Johannes, Gebert, Burkhard M, Helmke |
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| Rok vydání: | 2004 |
| Předmět: |
Adult
Male Heterozygote Genes APC Base Sequence Intracellular Signaling Peptides and Proteins Cell Cycle Proteins Exons Middle Aged Polymerase Chain Reaction Repressor Proteins Cytoskeletal Proteins Adenomatous Polyposis Coli Mutation Trans-Activators Humans Female Codon Colorectal Neoplasms Germ-Line Mutation beta Catenin Adaptor Proteins Signal Transducing DNA Primers |
| Zdroj: | Genes, chromosomescancer. 41(2) |
| ISSN: | 1045-2257 |
| Popis: | Patients with familial adenomatous polyposis coli (FAP) carry heterozygous mutations of the APC gene. At a young age, these patients develop multiple colorectal adenomas that consistently display a second somatic mutation in the remaining APC wild-type allele. Inactivation of APC leads to impaired degradation of beta-catenin, thereby promoting continuous cell-cycle progression. The role of APC inactivation in rare extracolonic tumors of FAP patients has not been characterized sufficiently. Among tissue specimen from 174 patients with known APC germ-line mutations, we identified 8 tumors infrequently seen in FAP. To investigate the pathogenic role of APC pathway deregulation in these lesions, they were analyzed for second-hit somatic mutations in the mutational cluster region of the APC gene. Immunohistochemistry was performed to compare the expression pattern of beta-catenin to the mutational status of the APC gene. Exon 3 of the beta-catenin gene (CTNNB1) was analyzed for activating mutations to investigate alternative mechanisms of elevated beta-catenin concentration. Although CTNNB1 mutations were not observed, second somatic APC mutations were found in 4 of the 8 tumors: a uterine adenocarcinoma, a hepatocellular adenoma, an adrenocortical adenoma, and an epidermal cyst. These tumors showed an elevated concentration of beta-catenin. No APC mutations were seen in focal nodular hyperplasia of the liver, angiofibrolipoma, and seborrheic wart. This is the first study reporting second somatic APC mutations in FAP-associated uterine adenocarcinoma and epidermal cysts. Furthermore, our data strengthen a role for impaired APC function in the pathogenesis of adrenal and hepatic neoplasms in FAP patients. |
| Databáze: | OpenAIRE |
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