SOMATIC MUTATIONS OF THE APC GENE IN SPORADIC HEPATOBLASTOMAS

Hepatoblastoma is a rare hepatic malignancy that occurs in children wi th an average age of 2 or 3 years and is known to be one of the extrac olonic manifestations of familial adenomatous polyposis. Only a single hepatoblastoma with a germ-line mutation of the adenomatous polyposis coli (APC) gene has been reported thus far, To elucidate the possible roles of APC gene alterations in sporadic hepatoblastomas, we examine d loss of heterozygosity (LOH) at the APC and MCC loci and performed a sequencing analysis of a part of the APC gene, including the mutation cluster region, in 13 hepatoblastomas of non-familial adenomatous pol yposis patients, LOH at the APC and/or MCC loci was observed in four o f seven (57%) informative cases. Of the 13 cases, somatic mutations we re detected in 8 (61.5%), with 9 (69%) cases showing genetic alteratio ns in the APC gene as LOH or somatic mutations, Two cases demonstrated double mutations. Furthermore, tile nature of the somatic mutations o bserved in the present study was unusual because 9 of the 10 mutations were missense, with only 1 case featuring a frame-shift mutation due to an insertion. Previous reports have described almost all (>90%) mut ations of the APC gene in colorectal tumors to result in a truncated A PC protein due to either frame-shift or nonsense mutations. These find ings suggest that a mutation of the APC gene may play an important rol e in the genesis of sporadic hepatoblastomas, and the mechanisms of AP C gene alteration may be different from those reported previously for colorectal tumors.