Epigenetic profiling of hepatoblastoma tumors with respect to low birth weight

肝母细胞瘤与低出生体重相关的表观遗传学分析

• 批准号: 8442993
• 负责人: Jenny N. Poynter
• 金额: $ 7.6万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442993
• 关键词: 15 year old; Aberrant DNA Methylation; Accounting; Adult; Affect; Age; Birth; Birth Weight; Cells; Characteristics; Child; Childhood; Childhood Liver Cancer; Cooperative Human Tissue Network; DNA; DNA Methylation; Data; Development; Diagnosis; Disease; Environmental Exposure; Epidemiologic Studies; Epigenetic Process; Etiology; Evaluation; Fetal Development; Freezing; Funding; Genes; Genome; Hepatoblastoma; Hypermethylation; IGF2 gene; Incidence; Infant; Knowledge; Lead; Liver; Liver neoplasms; Low Birth Weight Infant; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Methylation; Minnesota; Natural History; Normal tissue morphology; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Process; Promoter Regions; Relative (related person); Research; Resources; Risk; Risk Factors; Role; Sampling; Site; Specimen; Staging; Survival Rate; System; Tissues; Translating; Tumor Suppressor Genes; Tumor Tissue; United States; United States National Institutes of Health; Universities; Validation; Very Low Birth Weight Infant; base; cancer diagnosis; cancer type; carcinogenesis; early childhood; early life exposure; expectation; fetal; gene function; imprint; infancy; insight; novel; outcome forecast; premature; promoter; public health relevance; pyrosequencing; tumor; tumor initiation

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：肝母细胞瘤（HB）是一种罕见的肝肿瘤，在1975年至1999年在美国，其发病率翻了一番。 HB是儿童癌症最不可治疗形式的一种，相对生存率接近60％。最近的证据表明，低（LBW：1,500-2,500克）的HB风险增加，尤其是非常低的（VLBW：<1,500克）出生体重婴儿。存在有限的证据，以支持表观遗传改变在HB发展中的潜在作用；但是，迄今为止尚未进行HB甲基化模式改变的全面研究。我们的长期目标是了解表观遗传改变在HB中的作用，以及如何使用这些改变来告知治疗。这项研究的主要目的是鉴定一组基因，其基因在从84 Hb肿瘤和33个正常肝组织中提取的DNA中启动子高甲基化改变。我们的假设是，肿瘤和正常组织之间的DNA甲基化模式将有所不同，并将与生存有关。为了探讨这一假设，将评估以下特定目的：1）确定将肝母细胞瘤与正常肝组织区分开的甲基化特征，并评估诊断为HB后甲基化谱与结果之间的关联。作为探索目的，我们还将检查出出生体重低的情况与出生体重正常的情况下的DNA甲基化模式的差异。我们将利用两级方法来测量DNA甲基化。首先，我们将使用Illumina Human -Methylation450 Beadchip测量甲基化，在我们的发现40 hb和20个正常肝组织中，它在整个基因组中包括> 480,000 CpG基因座。这将使我们能够选择HB特征的CPG站点。然后，我们将通过在我们的44 hb和13个正常肝样品的验证集中进行焦磷酸测序来验证15个CPG位点。提出的研究完成时，我们期望我们将确定一组具有改变DNA甲基化的基因，这可能与HB的发展有关，并且与诊断后的生存有关。在本应用中提出的研究很重要，因为对HB中DNA甲基化的更全面评估，例如这里提出的一项可能会洞悉在这些肿瘤发展中发挥作用的途径。这些知识反过来可能会确定这种疾病儿童治疗的新靶标。