Molecular Epidemiology of Pediatric Germ Cell Tumors

儿童生殖细胞肿瘤的分子流行病学

• 批准号: 8470472
• 负责人: Jenny N. Poynter
• 金额: $ 65.86万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-10 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470472
• 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; Children' s Oncology Group; 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; Genotype; Germ Cells; Germ Lines; Germ cell tumor; Goals; Heritability; Heterogeneity; Histologic; Histology; Hypermethylation; Incidence; KITLG gene; Knowledge; Lead; Life; Life Style; Light; Literature; Mails; Malignant Childhood Germ Cell Tumor; Malignant Childhood Neoplasm; Malignant Neoplasms; Methylation; Molecular Epidemiology; Ovary; Parents; Pathway interactions; Pattern; 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; 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; migration; mouse model; novel; promoter; sex; tumor

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(申请人提供)：儿童生殖细胞肿瘤(GCTS)是一组不同种类的肿瘤，被认为是由于子宫内的事件而发生的，这表明正常胚胎发育所需过程的改变可能与病因学特别相关。近年来，儿童GCTS的发病率在某些亚组中有所增加，其潜在原因尚不清楚。考虑到发病年龄较早，遗传因素似乎是可能的。异常的DNA甲基化与多种癌症的病因有关，由于在胚系和正常发育的早期胚胎中发生了广泛的表观遗传重编程，因此在GCTS中具有特别相关的潜力。这项建议的主要目标是利用美国和加拿大的儿童肿瘤学小组(COG)和儿童癌症研究网络(CCRN)的资源，对儿童GCTS的遗传和表观遗传改变进行一项全面的病例-父母三合会研究。2008年7月1日至2015年12月31日期间确诊的0-19岁儿童GCT病例将通过CCRN确诊，并将被邀请参加。我们预计将招收大约930个案例。将从患者及其父母那里收集DNA样本，用于基因分析，获取肿瘤样本，以评估表观遗传变化，并通过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中的遗传变异将与儿童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，因此DNA甲基化模式将因肿瘤组织学而异。我们的主要目标将是：1)使用病例-双亲三联体设计，评估生殖细胞发育所涉及的关键途径中的遗传变异(包括所选基因的深度测序)与儿童GCT之间的关联；2)通过肿瘤组织学来探索DNA甲基化的异质性。我们将使用Illumina平台对相关生物途径的单核苷酸多态(SNPs)进行基因分型。候选SNP的选择将使用一种标签SNP方法，并辅之以先前报告的具有功能意义的SNP。此外，在我们的试点数据中，将使用深度重新测序来识别与儿科GCTS相关的四个基因的变异：KITLG、SPRY4、BAK1和DMRT1。我们将使用Illumina Human Methylation27珠芯片评估全基因组DNA甲基化，这将使我们能够选择具有GCTS特征的CpG位点。在这项申请中提出的研究具有重要意义，因为这将是迄今为止最大的儿科GCTS遗传流行病学研究，它将评估与遗传易感性有关的新关联。此外，了解儿科GCTS中的甲基化模式可能会提示肿瘤发生的发展阶段。