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.
Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Hendrik_Blaeker@med.uni-heidelberg.de
Hendrik
H
Bläker
Christian
C
Sutter
Martina
M
Kadmon
Herwart F
HF
Otto
Magnus
M
Von Knebel-Doeberitz
Johannes
J
Gebert
Burkhard M
BM
Helmke
D048868:Adaptor Proteins, Signal Transducing; D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics; D003062:Codon / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D017931:DNA Primers; D005091:Exons; D005260:Female; D017491:Genes, APC; D018095:Germ-Line Mutation / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; C411982:CTNNBIP1 protein, human; D018797:Cell Cycle Proteins; D003062:Codon; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin