Delineating the Role of Genetic Mutations in Hepatoblastoma Development and Phenotypes
Abstract
Hepatoblastoma is the most common liver neoplasm in children and accounts for approximately 1% of all childhood malignancies. Hepatoblastoma (HB) incidence has nearly doubled; faster than any other childhood cancer, while 5-year survival for hepatoblastoma is 59%-74%; one of the lowest survival rates for childhood cancer. Therefore, an improved understanding of the mechanisms underlying this cancer will enable the development of improved and more targeted clinical therapies. HB is an embryonal tumor with distinct phenotypes and whose classification and treatment is guided largely by both microscopic appearance and marker expression. The molecular defects present in HB have been identified, and RNA analyses of HB tumors have revealed associations of CTNNB1 (a specific gene) mutations, with two tumor subtypes, embryonal and fetal HB, resembling distinct phases of liver development, with the former associated with worse prognosis. These findings suggest a functional role for mutations recurrent in HB, impacting tumor behavior and patient outcome, and the need for studies evaluating the role of CTNNB1 mutations in liver development and HB tumorigenesis. Research of HB has historically been challenging. Beyond our limited understanding of the disease, its rarity makes access to patient samples difficult. Furthermore, current models to study HB fail to mimic the liver cancer, largely consisting of cell lines and mouse models. These systems are limited, as they are either focused on tissue culture adapted cell lines (e.g., by being in culture for a long time they have changed significantly from the tumor from which they were derived) or tumors that form after genetic manipulation in adult mice (e.g., which do not mimic the human disease). These models also lack the ability to functionally study early stages of cancer development and do not faithfully recapitulate the human tumor microenvironment. Our proposal aims to address the current limitations in studying HB by collaborating with other institutes in order to obtain a large enough cohort needed to provide a comprehensive disease-specific data set of HB. We will couple this data with a stem cell-derived liver tumor model that we have shown mimics HB tumors. Together, our efforts will generate an unprecedented toolkit that we will then use to interrogate the impact of specific mutations at different stages of liver development, and use this to interrogate their impact on HB development. Together, our proposal directly addresses a Fiscal Year 2020 Rare Cancer Research Program (RCRP) Focus Area by focusing on a rare cancer HB that affects less than 6 persons per 100,000 per year, while addressing two RCRP Focus Areas of biology and etiology and research models. This proposal will fill an important gap currently present in HB research by providing an invaluable HB dataset, utilizing a model that enables determining the impact of the time at which CTNNB1 alterations are introduced in HB development, and developing models of HB subtypes essential for studies and identification of novel therapies which will have clinically relevant impact in the near-term.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110978
Entities
People
- Robert E. Schwartz
Organizations
- United States Army
- Weill Cornell Medicine