title: Sporadic childhood hepatoblastomas show activation of beta-catenin, mismatch repair defects and p53 mutations.
abstract: Hepatoblastoma, a rare embryonic tumor that may arise sporadically or in the context of hereditary syndromes (familial adenomatous polyposis and Beckwith-Wiedemann's) is the most frequent liver cancer of childhood. Deregulation of the APC/beta-catenin pathway occurs in a consistent fraction of hepatoblastomas, with mutations in the APC and beta-catenin genes implicated in familial adenomatous polyposis-associated and sporadic hepatoblastomas, respectively. Alterations in other cancer-related molecular pathways have not been reported. We investigated a series of 21 sporadic paraffin-embedded hepatoblastoma cases for mutations in the p53 (exons 5-8) and beta-catenin (exon 3) genes, loss of heterozygosity at APC, microsatellite instability and immunohistochemical expression of beta-catenin and of the two main mismatch repair proteins, MLH1 and MSH2. No loss of heterozygosity at APC was detected. We found mutations in beta-catenin and p53 in 4/21 (19%) and 5/21 (24%) cases respectively, beta-catenin protein accumulation in 14/21 cases (67%), microsatellite instability in 17/21 cases (81%), of which eight resulted positive for high-level of microsatellite instability (in four cases associated with loss of MLH1/MSH2 immunostaining). No correlations between involved molecular pathway(s) and hepatoblastoma histotype(s) emerged. This study confirms that beta-catenin deregulation is involved in sporadic hepatoblastoma and also suggests that mismatch repair defects and p53 mutations contribute to this rare liver cancer. Sporadic hepatoblastoma appears to be molecularly and phenotypically heterogeneous and may reflect different pathways of liver carcinogenesis.
authors.affiliation: Department of Oncology, University of Chieti-Pescara, Chieti, Italy. mc.curia@unich.it
authors.forename: Maria C
authors.initials: MC
authors.lastname: Curia
authors.forename: Michele
authors.initials: M
authors.lastname: Zuckermann
authors.forename: Laura
authors.initials: L
authors.lastname: De Lellis
authors.forename: Teresa
authors.initials: T
authors.lastname: Catalano
authors.forename: Rossano
authors.initials: R
authors.lastname: Lattanzio
authors.forename: Gitana
authors.initials: G
authors.lastname: Aceto
authors.forename: Serena
authors.initials: S
authors.lastname: Veschi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cama
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Otte
authors.forename: Mauro
authors.initials: M
authors.lastname: Piantelli
authors.forename: Renato
authors.initials: R
authors.lastname: Mariani-Costantini
authors.forename: Francesco
authors.initials: F
authors.lastname: Cetta
authors.forename: Pasquale
authors.initials: P
authors.lastname: Battista
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D018197:Hepatoblastoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008113:Liver Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000032:analysis; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051176:beta Catenin / Q000032:analysis / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein