A pilot study of DNA methylation in pediatric germ cell tumors

儿科生殖细胞肿瘤 DNA 甲基化的初步研究

• 批准号: 7893167
• 负责人: Jenny N. Poynter
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-14 至 2011-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893167
• 关键词: Aberrant DNA Methylation; Adult; Age; Cell division; Characteristics; Child; Childhood Germ Cell Tumor; Children' s Oncology Group; DNA; DNA Methylation; Data; Development; Diagnosis; Embryo; Environmental Exposure; Environmental Risk Factor; Epidemiologic Studies; Epigenetic Process; Etiology; Event; Fertilization; Fetal Development; Future; Genes; Genome; Genomic Imprinting; Genomic Instability; Genomics; Germ Cells; Germ Lines; Germ cell tumor; Germinoma; Goals; Gonadal structure; Grant; Heterogeneity; Histologic; Histology; Hypermethylation; Knowledge; Lead; Life; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Methylation; Mitotic; Modification; Molecular Epidemiology; Normal tissue morphology; Oncogenes; Pathology; Pattern; Pilot Projects; Play; Promoter Regions; Research; Research Personnel; Role; Sampling; Site; Staging; Structure of primordial sex cell; Teratoma; Testicular Germ Cell Tumor; Tumor Pathology; Tumor Suppressor Genes; United States National Institutes of Health; Yolk Sac Tumor; base; cancer epidemiology; cancer type; carcinogenesis; disorder risk; early life exposure; epidemiologic data; epidemiology study; expectation; fetal; gene function; genetic epidemiology; imprint; in utero; insight; promoter; public health relevance; sex; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Pediatric germ cell tumors (GCTs) are a heterogeneous group of tumors that are hypothesized to occur as a result of events in utero, although the etiology remains largely unknown. Aberrant DNA methylation, which has been implicated in the etiology of multiple types of cancer, has the potential to be especially relevant in GCTs due to the extensive epigenetic reprogramming that occurs in the germ line and early embryo during normal development. Limited evidence exists to support a potential role of epigenetic alterations in the development of GCTs; however, a comprehensive study of alterations in methylation patterns in pediatric GCTs has not been conducted to date. Our long term objective is to understand the role of epigenetic alterations in pediatric GCTs and how these alterations may be influenced by environmental exposures, with the goal of establishing a large genetic epidemiology study of pediatric GCT in the Children's Oncology Group. The primary objective for this pilot is to identify a panel of genes with altered promoter hypermethylation in DNA extracted from 58 pediatric GCTs, including germinomas, yolk sac tumors, teratomas and mixed germ cell tumors, overall and by histologic type. Our hypothesis is that DNA methylation in genes previously implicated in carcinogenesis will differ between tumor and normal tissue and also by tumor histology. To explore this hypothesis, the following specific aims will be evaluated: 1) identify genes with altered promoter hypermethylation in pediatric GCTs and 2) explore inter- and intratumoral heterogeneity in DNA methylation by tumor histology. We will evaluate DNA methylation using a two-staged approach. First, we will measure DNA methylation in a panel of 807 genes previously implicated in carcinogenesis using the Illumina GoldenGate Methylation Cancer Panel, which will allow us to select CpG sites that are characteristic of GCTs. We will then validate and expand the top15 CpG sites by Pyrosequencing on the same 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 pediatric GCT, and that these data will be included as preliminary data in an NIH R01 application to collect additional tumor and epidemiologic data for a study of the epigenetics of pediatric GCT. The research proposed in this application is significant because it will provide a more comprehensive understanding of DNA methylation in pediatric GCT in cancer-related genes throughout the genome as well as in tumors of different histologic subtypes. PUBLIC HEALTH RELEVANCE: Environmental exposures during fetal development and early life are thought to play a role in the development of cancer in both children and adults, although the mechanism by which these exposures influence disease risk is not clear. Extensive epigenetic reprogramming occurs immediately after fertilization (in the germ cells), and these epigenetic modifications are generally stable throughout the lifetime of mitotic cell divisions. 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 the fetal origins of carcinogenesis. The overall objective of this pilot grant is to evaluate epigenetic alterations in pediatric germ cell tumors, which will be used as pilot data for a future epidemiologic study of this important and under- investigated cancer.

描述（由申请人提供）： 儿科生殖细胞肿瘤 (GCT) 是一组异质性肿瘤，被认为是由于子宫内事件而发生的，尽管其病因仍然很大程度上未知。异常的 DNA 甲基化与多种癌症的病因学有关，由于在正常发育过程中种系和早期胚胎中发生广泛的表观遗传重编程，异常 DNA 甲基化有可能与 GCT 特别相关。支持表观遗传改变在 GCT 发展中的潜在作用的证据有限；然而，迄今为止尚未对儿科 GCT 甲基化模式的变化进行全面研究。我们的长期目标是了解表观遗传改变在儿科 GCT 中的作用以及这些改变如何受到环境暴露的影响，目标是在儿童肿瘤学组中建立一项针对儿科 GCT 的大型遗传流行病学研究。该试验的主要目标是从 58 个儿科 GCT 中提取的 DNA 中鉴定一组启动子高甲基化发生改变的基因，包括生殖细胞瘤、卵黄囊肿瘤、畸胎瘤和混合生殖细胞肿瘤（整体和按组织学类型）。我们的假设是，先前与癌发生有关的基因中的 DNA 甲基化在肿瘤和正常组织之间以及肿瘤组织学方面会有所不同。为了探索这一假设，将评估以下具体目标：1）识别儿科 GCT 中启动子高甲基化改变的基因，2）通过肿瘤组织学探索肿瘤间和肿瘤内 DNA 甲基化的异质性。我们将使用两阶段方法评估 DNA 甲基化。首先，我们将使用 Illumina GoldenGate 甲基化癌症面板测量一组先前与癌发生有关的 807 个基因中的 DNA 甲基化，这将使我们能够选择具有 GCT 特征的 CpG 位点。然后，我们将通过焦磷酸测序对相同样品验证并扩展前 15 个 CpG 位点。在完成拟议的研究后，我们期望我们将鉴定出一组 DNA 甲基化改变的基因，这些基因可能与儿科 GCT 的发展相关，并且这些数据将作为初步数据纳入 NIH R01 申请中，以收集更多肿瘤和流行病学数据，用于儿科 GCT 表观遗传学研究。本申请中提出的研究意义重大，因为它将提供对儿科 GCT 中整个基因组中癌症相关基因以及不同组织学亚型肿瘤中 DNA 甲基化的更全面的了解。 公共卫生相关性：胎儿发育和早期生命期间的环境暴露被认为在儿童和成人癌症的发展中发挥着作用，尽管这些暴露影响疾病风险的机制尚不清楚。广泛的表观遗传重编程在受精后（在生殖细胞中）立即发生，并且这些表观遗传修饰在有丝分裂细胞分裂的整个生命周期中通常是稳定的。更好地了解这些表观遗传变化可能会为生命早期暴露如何导致基因功能的长期改变提供一些见解，并可能为致癌的胎儿起源提供重要见解。该试点拨款的总体目标是评估儿科生殖细胞肿瘤的表观遗传改变，这将用作未来对这种重要且尚未研究的癌症的流行病学研究的试点数据。