title: Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors.
abstract: Hepatoblastoma is characterized by a diversity of differentiation patterns, some resembling stages of liver development, and occasionally associated with clinical behavior. Our hypothesis is that histologic microheterogeneity in hepatoblastoma correlates with molecular heterogeneity and reflects different stages of developmental arrest. We studied the activation status of the Wnt and Notch pathways and the differential expression of hepatocyte nuclear factor 4alpha, EGFR, and IGF2 genes, relevant to liver development and malignant transformation in histologic variants of hepatoblastoma. Eighty-seven percent of 32 hepatoblastoma cases studied carried CTNNB1 mutations within the ubiquitination domain. Large deletions were seen only in pure fetal cases, also characterized by CCND1 and GLUL (GS) overexpression. Hepatoblastomas with small-cell type appeared clearly distinct and were the only ones with negative GLUL expression. HES1 expression and HES1/AXIN2 used to measure Notch versus Wnt activation ratio were particularly elevated in pure fetal cases and were lowest in hepatoblastomas with small-cell component. Hepatocyte nuclear factor 4alpha was relatively elevated only in embryonal hepatoblastomas. DLK1, DKK, AXIN2, IGF2, and EGFR were increased in all subtypes. Our results support the hypothesis that hepatoblastoma microheterogeneity correlates with molecular heterogeneity. DLK1, a marker of bipotential oval cells, is consistently up-regulated in hepatoblastoma. Therefore, we speculate that hepatoblastomas may arise from a proliferating bipotential precursor. Wnt activation is prevalent in hepatoblastomas, most significantly in predominantly embryonal and mixed types, whereas Notch activation, needed for cholangiocytic differentiation at a more differentiated state, is highest in pure fetal hepatoblastomas. The relative Wnt versus Notch activation appears useful in stratifying different subtypes.
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA. doloresl@bcm.edu
authors.forename: Dolores
authors.initials: D
authors.lastname: López-Terrada
authors.forename: Preethi H
authors.initials: PH
authors.lastname: Gunaratne
authors.forename: Adekunle M
authors.initials: AM
authors.lastname: Adesina
authors.forename: Joseph
authors.initials: J
authors.lastname: Pulliam
authors.forename: David M
authors.initials: DM
authors.lastname: Hoang
authors.forename: Yummy
authors.initials: Y
authors.lastname: Nguyen
authors.forename: Toni-Ann
authors.initials: TA
authors.lastname: Mistretta
authors.forename: Judith
authors.initials: J
authors.lastname: Margolin
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002135:Calcium-Binding Proteins; D002648:Child; D002675:Child, Preschool; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D018197:Hepatoblastoma / Q000235:genetics* / Q000473:pathology; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D000072056:Transcription Factor HES-1; D051153:Wnt Proteins / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D066246:ErbB Receptors; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; D007335:Insulin-Like Growth Factor II; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000072056:Transcription Factor HES-1; D051153:Wnt Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human; C512941:DLK1 protein, human; C496592:HNF4A protein, human; C035170:IGF2 protein, human; C078493:HES1 protein, human; C512478:EGFR protein, human