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: 8182074
• 负责人: Jenny N. Poynter
• 金额: $ 60.16万
• 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/8182074
• 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; 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. PUBLIC HEALTH RELEVANCE: Pediatric germ cell tumors (GCTs) are cancers that affect approximately 360 children per year; the incidence rates for some pediatric GCTs are rising. Little is known about why these types of cancers develop in children, but it is possible that abnormalities in underlying genetic processes that occur during fetal development play a role. We are proposing the largest molecular epidemiology study ever conducted to evaluate the contribution of underlying genetic susceptibility to the development of pediatric GCT. Our goal is to provide important insights on how early-life events may lead to long-term alterations in gene function and increase the risk of cancer.

描述（由申请方提供）：儿科生殖细胞肿瘤（GCT）是一组异质性肿瘤，假设其是子宫内事件的结果，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，在某些亚组中，儿科GCT的发生率有所增加，其根本原因尚不清楚。考虑到发病年龄较早，遗传贡献似乎是可能的。异常DNA甲基化与多种类型癌症的病因学有关，由于在正常发育期间在生殖系和早期胚胎中发生的广泛的表观遗传重编程，其在GCT中具有特别相关的潜力。本提案的主要目的是利用美国和加拿大儿童肿瘤学小组（COG）和儿童癌症研究网络（CCRN）的资源，对儿童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。将通过CCRN确定2008年7月1日至2015年12月31日诊断的儿科GCT（0-19岁）病例，并邀请其参加。我们预计将招募约930例病例。将从病例及其父母中收集DNA样本用于遗传分析，将获得肿瘤标本用于评价表观遗传学改变，并将使用邮寄问卷评估生活方式和环境风险因素。我们假设生殖细胞发育相关的关键通路的遗传变异与儿科GCT相关。我们进一步假设，因为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关键途径中的遗传变异（包括选定基因的深度测序）与儿科GCT之间的关联; 2）通过肿瘤组织学探索DNA甲基化的异质性。我们将使用Illumina平台对相关生物学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，该方法补充了先前已报告具有功能意义的SNP。此外，深度重测序将用于识别与我们的试点数据中的儿科GCT相关的四个基因中的变体，即KITLG、SPRY 4、BAK 1和DMRT 1。我们将使用Illumina HumanMethylation 27 BeadChip评估全基因组DNA甲基化，这将使我们能够选择GCT特征性的CpG位点。本申请中提出的研究具有重要意义，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有关的新关联。此外，了解儿童GCT中的甲基化模式可能表明肿瘤发生的发育阶段。 公共卫生相关性：儿科生殖细胞肿瘤（GCT）是每年影响大约360名儿童的癌症;一些儿科GCT的发病率正在上升。关于这些类型的癌症在儿童中发展的原因知之甚少，但在胎儿发育期间发生的潜在遗传过程异常可能起作用。我们正在进行有史以来最大规模的分子流行病学研究，以评估潜在的遗传易感性对儿科GCT发展的贡献。我们的目标是提供关于生命早期事件如何导致基因功能长期改变并增加癌症风险的重要见解。