Analysis of somatic APC mutations in rare extracolonic tumors of patients with familial adenomatous polyposis coli.

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.

Bläker H ，Sutter C ，Kadmon M ，Otto HF ，Von Knebel-Doeberitz M ，Gebert J ，Helmke BM ... -  《GENES CHROMOSOMES & CANCER》

Refining the relation between 'first hits' and 'second hits' at the APC locus: the 'loose fit' model and evidence for differences in somatic mutation spectra among patients.

Crabtree M ，Sieber OM ，Lipton L ，Hodgson SV ，Lamlum H ，Thomas HJ ，Neale K ，Phillips RK ，Heinimann K ，Tomlinson IP ... -  《ONCOGENE》

A beta-catenin mutation in a sporadic colorectal tumor of the RER phenotype and absence of beta-catenin germline mutations in FAP patients.

Müller O ，Nimmrich I ，Finke U ，Friedl W ，Hoffmann I ... -  《GENES CHROMOSOMES & CANCER》

Germline APC mutation on the beta-catenin binding site is associated with a decreased apoptotic level in colorectal adenomas.

Venesio T ，Balsamo A ，Scordamaglia A ，Bertolaso M ，Arrigoni A ，Sprujevnik T ，Rossini FP ，Risio M ... -  《MODERN PATHOLOGY》

Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors.

Miyaki M ，Konishi M ，Kikuchi-Yanoshita R ，Enomoto M ，Igari T ，Tanaka K ，Muraoka M ，Takahashi H ，Amada Y ，Fukayama M ... -  《CANCER RESEARCH》