Molecular Epidemiology of Pediatric Germ Cell Tumors

儿童生殖细胞肿瘤的分子流行病学

基本信息

批准号：
8856511
负责人：
Jenny N. Poynter
金额：
$ 77.6万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-10 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8856511
关键词：
129/Sv Mouse Aberrant DNA Methylation Adult Affect Age Age of Onset Apoptosis BAK1 gene Biological Canada Cancer Etiology Cancer Research Network Cell Cycle Regulation Cells Characteristics Child Childhood Childhood Germ Cell Tumor DNA DNA Methylation DNA Resequencing Data Development Diagnosis Embryo Embryonic Development Enrollment Environmental Exposure Environmental Risk Factor Epigenetic Process Etiology Evaluation Event Fetal Development Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Processes Genetic Variation Genetic study Genotype Germ Cells Germ Lines Germ cell tumor Goals Heritability Heterogeneity Histologic Histology Hypermethylation Incidence KITLG gene Knowledge Lead Life Life Style Light Literature Malignant Childhood Germ Cell Tumor Malignant Childhood Neoplasm Malignant Neoplasms Methylation Molecular Epidemiology Ovary Parents Pathway interactions Pediatric Oncology Group Play Predisposition Process Questionnaires Reporting Research Resources Risk Role Sampling Single Nucleotide Polymorphism Site Specimen Staging Structure of primordial sex cell Subgroup Susceptibility Gene Testicular Germ Cell Tumor Testis Time Triad Acrylic Resin Tumor Subtype Tumor Suppressor Genes United States Variant Yolk Sac bead chip cancer risk cancer type carcinogenesis cell motility deep sequencing design epidemiology study fetal gene function genetic analysis genetic epidemiology genetic variant genome wide association study genome-wide in utero insight interest methylation pattern migration mouse model novel promoter sex tumor

项目摘要

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, which suggests that alterations in processes required for normal embryonic development are likely to be especially relevant to etiology. The incidence of pediatric GCTs has increased in recent years in certain subgroups, and the underlying causes are unknown. Given the early age of onset, genetic contributions seem likely. 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. The primary objective for this proposal is to conduct a comprehensive case-parent triad study of genetic and epigenetic alterations in pediatric GCTs using the resources of the Children's Oncology Group (COG) and the Childhood Cancer Research Network (CCRN) in the United States and Canada. Cases of pediatric GCT (ages 0-19 years) diagnosed from July 1, 2008-December 31, 2015 will be identified through the CCRN and will be invited to participate. We expect to enroll approximately 930 cases. DNA samples will be collected from the cases and their parents for use in genetic analyses, tumor specimens will be obtained for evaluation of epigenetic alterations, and lifestyle and environmental risk factors will be assessed using mailed questionnaires. We hypothesize that genetic variation in key pathways relevant to germ cell development will be associated with pediatric GCT. We further hypothesize that because the histologic subtype of the tumor is dependent on the degree of differentiation that has occurred at the time of transformation, DNA methylation patterns will differ by tumor histology. Our primary aims will be to: 1) Evaluate associations between genetic variation (including deep sequencing of selected genes) in key pathways involved in germ cell development and pediatric GCT using a case-parent triad design and 2) Explore heterogeneity in DNA methylation by tumor histology. We will genotype single nucleotide polymorphisms (SNPs) from relevant biological pathways using the Illumina platform. Candidate SNPs will be selected using a tagSNP approach supplemented with SNPs that have been previously reported to have functional significance. In addition, deep re-sequencing will be used to identify variants in four genes that are associated with pediatric GCTs in our pilot data, KITLG, SPRY4, BAK1, and DMRT1. We will evaluate genome wide DNA methylation using the Illumina HumanMethylation27 BeadChip, which will allow us to select CpG sites that are characteristic of GCTs. The research proposed in this application is significant because it will be the largest genetic epidemiology study of pediatric GCTs to date and it will evaluate novel associations with respect to genetic susceptibility. In addition, understanding methylation patterns in pediatric GCTs may indicate the developmental stage at which the tumor arose.

描述（由申请人提供）：小儿生殖细胞肿瘤（GCT）是一组异质性肿瘤，假设是由于子宫内事件而发生的，这表明正常胚胎发育所需过程的改变可能特别相关到病因学。近年来，某些亚组儿童 GCT 的发病率有所增加，但其根本原因尚不清楚。鉴于发病年龄较早，遗传因素似乎是有可能的。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。该提案的主要目标是利用美国和加拿大儿童肿瘤学组 (COG) 和儿童癌症研究网络 (CCRN) 的资源，对儿科 GCT 的遗传和表观遗传改变进行全面的病例父母三联体研究。 2008年7月1日至2015年12月31日诊断的儿童GCT病例（0-19岁）将通过CCRN进行鉴定，并受邀参加。我们预计将招募约 930 例。将从病例及其父母处采集DNA样本用于遗传分析，获取肿瘤样本用于评估表观遗传改变，并使用邮寄问卷评估生活方式和环境风险因素。我们假设与生殖细胞发育相关的关键途径的遗传变异将与儿科 GCT 相关。我们进一步假设，由于肿瘤的组织学亚型取决于转化时发生的分化程度，DNA 甲基化模式将因肿瘤组织学而异。我们的主要目标是：1) 使用病例亲本三联体设计评估生殖细胞发育和儿科 GCT 所涉及的关键途径中遗传变异（包括选定基因的深度测序）之间的关联，以及 2) 探索肿瘤 DNA 甲基化的异质性组织学。我们将使用 Illumina 平台对相关生物途径的单核苷酸多态性 (SNP) 进行基因分型。将使用 tagSNP 方法选择候选 SNP，并辅以先前报道的具有功能意义的 SNP。此外，深度重测序将用于识别我们的试点数据中与儿科 GCT 相关的四个基因的变异：KITLG、SPRY4、BAK1 和 DMRT1。我们将使用 Illumina HumanMmethylation27 BeadChip 评估全基因组 DNA 甲基化，这将使我们能够选择具有 GCT 特征的 CpG 位点。本申请中提出的研究意义重大，因为它将是迄今为止最大的儿科 GCT 遗传流行病学研究，并将评估与遗传易感性方面的新关联。此外，了解儿科 GCT 的甲基化模式可能表明肿瘤发生的发育阶段。