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Childhood Hepatoblastomas Frequently Carry a Mutated Degradation Targeting Box of the ß-Catenin Gene¹

Department of Neuropathology, University of Bonn Medical Center, D-53105 Bonn, Germany [A. K., D. D., T. P.]; Department of Pathology, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, H3T 1E2, Canada [S. A.]; Department of Pediatric Pathology, University of Kiel, D-24105 Kiel, Germany [I. L.]; Department of Pediatric Surgery, Hannover Medical School, D-30625 Hannover, Germany [D. v. S.]

Hepatoblastomas (HBs) are embryonal tumors affecting young children and representing the most frequent malignant liver tumors in childhood. The molecular pathogenesis of HB is poorly understood. Although most cases are sporadic, the incidence is highly elevated in patients with familial adenomatous polyposis coli. These patients carry germline mutations of the APC tumor suppressor gene. APC controls the degradation of the oncogene product ß-catenin after its NH₂-terminal phosphorylation on serine/threonine residues. APC, as well as ß-catenin, has been found to be a central effector of the growth promoting wingless signaling pathway in development. To find out if this pathway is involved in the pathogenesis of sporadic HBs, we examined 52 biopsies and three cell lines from sporadic HBs for mutations in the APC and ß-catenin genes. Using single-strand conformational polymorphism analysis, deletion screening by PCR, and direct sequencing, we found a high frequency of ß-catenin mutations in sporadic HBs (48%). The mutations affected exon 3 encoding the degradation targeting box of ß-catenin leading to accumulation of intracytoplasmic and nuclear ß-catenin protein. The high frequency of activating mutations in the ß-catenin gene indicates an important role in the pathogenesis of HB.

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