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

基本信息

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
项目类别：
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

项目摘要

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）是一种罕见的肝脏肿瘤，其发病率在 1975 年至 1999 年间在美国翻了一番。 HB 是最难治疗的儿童癌症之一，5 年相对生存率接近 60%。最近的证据表明，低出生体重（LBW：1,500-2,500 克），特别是极低出生体重（VLBW：<1,500 克）婴儿患 HB 的风险增加。有限的证据支持表观遗传改变在 HB 发展中的潜在作用；然而，迄今为止尚未对 HB 甲基化模式的变化进行全面研究。我们的长期目标是了解 HB 表观遗传改变的作用以及如何利用这些改变来指导治疗。本研究的主要目的是鉴定从 84 个 HB 肿瘤和 33 个正常肝组织中提取的 DNA 中启动子高甲基化发生改变的一组基因。我们的假设是，肿瘤组织和正常组织之间的 DNA 甲基化模式会有所不同，并且与生存相关。为了探索这一假设，将评估以下具体目标：1）确定区分肝母细胞瘤与正常肝组织的甲基化谱，2）评估甲基化谱与 HB 诊断后结果之间的关联。作为探索性目标，我们还将检查低出生体重病例与正常出生体重病例的 DNA 甲基化模式差异。我们将利用两阶段方法来测量 DNA 甲基化。首先，我们将使用 Illumina HumanMmethylation450 BeadChip 测量甲基化，该芯片在我们的 40 个 HB 和 20 个正常肝组织的发现组中包括整个基因组中超过 480,000 个 CpG 位点。这将使我们能够选择具有 HB 特征的 CpG 位点。然后，我们将通过焦磷酸测序在 44 个 HB 和 13 个正常肝脏样本的验证集中验证前 15 个 CpG 位点。在完成拟议的研究后，我们期望我们能够鉴定出一组 DNA 甲基化发生改变的基因，这些基因可能与 HB 的发展相关，并与诊断后的生存相关。本申请中提出的研究意义重大，因为对 HB 中 DNA 甲基化进行更全面的评估（例如本文提出的评估）可能会深入了解在这些肿瘤的发展中发挥作用的途径。这些知识反过来可能会确定治疗患有这种疾病的儿童的新目标。