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

✍ Scribed by Hendrik Bläker; Christian Sutter; Martina Kadmon; Herwart F. Otto; Magnus von Knebel-Doeberitz; Johannes Gebert; Burkhard M. Helmke

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 230 KB
• Volume: 41
• Category: Article
• ISSN: 1045-2257
• DOI: 10.1002/gcc.20071

✦ Synopsis

Abstract

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 β‐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 β‐catenin to the mutational status of the APC gene. Exon 3 of the β‐catenin gene (CTNNB1) was analyzed for activating mutations to investigate alternative mechanisms of elevated β‐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 β‐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. © 2004 Wiley‐Liss, Inc.