The Manton Center for Orphan Disease Research

Laurie Jackson-Grusby, PhD

Modeling Syndromic Hepatoblastoma

The pediatric liver tumor hepatoblastoma occurs in three rare syndromes afflicting children, and the tumors have been associated with the corresponding genetic and epigenetic lesions. Namely, Wnt pathway activation in Gardener's Syndrome, loss of imprinting (LOI) and/or loss of heterozygosity (LOH) at 11p15 in Beckwith-Weideman Syndrome (BWS), and p53 LOH in Li-Fraumeni Syndrome have all been associated with hepatoblastomas. Based on gene expression profiling and histopathology, distinct clinical subtypes of hepatoblastoma have been reported. While prognosis following surgical resection and chemotherapy is curative for certain patients, relapsing disease is poorly managed for those patients with residual disease. The current leading hypothesis is that the relapsing disease relates to the combination of mutations and/or the cell of origin of the incipient mutations. We propose to test this hypothesis by using a combination of epigenomic profiling of human tumors, and developmental genetic analysis in a mouse model. Our approach will generate new animal models using combinations of mutations that occur in the three rare syndromes using conditional mouse genetics and customized mouse embryonic stem cell modeling. Current mouse models for hepatoblastoma rely on chemical induction, or forced overexpression of oncogenes that have not been directly associated with hepatoblastoma. Therefore, a more precise animal model is needed to faithfully recapitulate the genetic and epigenetic lesions found in relapsing tumors. Because our knowledge of the genetic and epigenomic lesions of these rare tumors has focussed solely on these three known pathways, we will take a sequence based approach to determine DNA methylation genome-wide in tumors. This study will also leverage a Department of Pathology effort to characterize novel mutations using a mutational hotspot screen, "OncoMap." Together, these approaches will define new molecular characteristics of hepatoblastoma, and assess the developmental consequences of the three primary causative mutations on hepatic differentiation and tumorigenesis.