Childhood hepatoblastomas frequently carry a mutated degradation targetingbox of the beta-catenin gene

Hepatoblastomas (HBs) are embryonal tumors affecting young children and rep resenting the most frequent malignant liver tumors in childhood. The molecu lar pathogenesis of HE is poorly understood. Although most cases are sporad ic, the incidence is highly elevated in patients with familial adenomatous polyposis coli. These patients carry germline mutations of the APC tumor su ppressor gene. APC controls the degradation of the oncogene product beta-ca tenin after its NH2-terminal phosphorylation on serine/threonine residues. APC, as well as beta-catenin, has been found to be a central effector of th e growth promoting wingless signaling pathway in development. To find out i f 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 AP C and beta-catenin genes. Using single-strand conformational polymorphism a nalysis, deletion screening by PCR, and direct sequencing, we found a high frequency of beta-catenin mutations in sporadic HBs (48%), The mutations af fected exon 3 encoding the degradation targeting box of beta-catenin leadin g to accumulation of intracytoplasmic and nuclear beta-catenin protein. The high frequency of activating mutations in the beta-catenin gene indicates an important role in the pathogenesis of HE.