Hepatoblastoma (HB) is a rare liver tumor, the incidence of which doubled between 1975 and 1999 in the United States. HB is one of the least treatable forms of childhood cancer with 5-year relative survival rates near 60%. Recent evidence suggests increased risk of HB in low (LBW: 1,500-2,500 grams), and especially very low (VLBW: <1,500 grams) birth weight infants. Limited evidence exists to support a potential role of epigenetic alterations in the development of HB;however, a comprehensive study of alterations in methylation patterns in HB has not been conducted to date. Our long term objective is to understand the role of epigenetic alterations in HB and how these alterations may be used to inform treatment. The primary objective for this study is to identify a panel of genes with altered promoter hypermethylation in DNA extracted from 84 HB tumors and 33 normal liver tissues. Our hypothesis is that DNA methylation patterns will differ between tumor and normal tissue and will be associated with survival. To explore this hypothesis, the following specific aims will be evaluated: 1) identify methylation profiles that distinguish hepatoblastoma from normal liver tissue and 2) evaluate the association between methylation profiles and outcomes following a diagnosis of HB. As an exploratory aim, we will also examine differences in DNA methylation patterns in cases with low birth weight vs. cases with normal birth weight. We will utilize a two-staged approach to measure DNA methylation. First, we will measure methylation using the Illumina HumanMethylation450 BeadChip, which includes >480,000 CpG loci throughout the genome, in our discovery set of 40 HB and 20 normal liver tissues. This will allow us to select CpG sites that are characteristic of HB. We will then validate the top 15 CpG sites by pyrosequencing in our validation set of 44 HB and 13 normal liver samples. At the completion of the proposed studies, it is our expectation that we will have identified a panel of genes with altered DNA methylation that are likely to be relevant in the development of HB and associated with survival following diagnosis. The research proposed in this application is significant because a more comprehensive evaluation of DNA methylation in HB such as the one proposed here may provide insight into the pathways that play a role in the development of these tumors. This knowledge in turn may identify new targets for therapy in children with this disease.

Public Health Relevance

Hepatoblastoma (HB) is a rare pediatric liver cancer that affects approximately 100 children per year in the United States;the incidence rate for HB doubled from 1975-1999. Little is known about why these types of cancers develop in children, but it is possible that abnormalities in processes that occur during fetal development play a role. In support of this hypothesis, low birth weight has emerged as a strong risk factor for HB. We are proposing a comprehensive evaluation of DNA methylation in these tumors. A better understanding of these epigenetic changes may provide some insights on how early-life exposures lead to long-term alterations in gene function, and may provide important insights into potential new targets for treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Special Emphasis Panel (ZCA1-SRLB-D (O1))
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Verma, Mukesh
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University of Minnesota Twin Cities
Schools of Medicine
United States
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