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（由申请人提供）：小儿生殖细胞肿瘤（GCTS）是一组异质的肿瘤组，由于子宫内事件的原因是发生，这表明正常胚胎发育所需的过程改变可能与病因特别相关。近年来，在某些亚组中，小儿GCT的发生率有所增加，而潜在的原因尚不清楚。鉴于发病年龄，遗传贡献似乎很可能。异常的DNA甲基化与多种类型的癌症的病因有关，由于在正常发育过程中在生殖线和早期胚胎中发生的广泛表观遗传重编程，因此在GCT中特别相关。该提案的主要目的是使用儿童肿瘤学组（COG）和美国和加拿大的儿童肿瘤学小组（CCOG）和儿童癌症研究网络（CCRN）进行全面的病例父母三合会研究。从2008年7月1日至12月31日诊断为2015年7月1日诊断为2015年7月1日的小儿GCT病例（年龄为0-19岁），将通过CCRN确定，并邀请参加。我们预计将注册约930例。将从病例中收集DNA样本，其父母用于遗传分析，将获得肿瘤标本以评估表观遗传改变，并将使用邮寄问卷调查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小儿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有所不同。我们的主要目的是：1）使用病细胞发育和小儿GCT中的关键途径评估遗传变异（包括对选定基因的深度测序），使用病例父母三合会设计和2）探索肿瘤组织学中DNA甲基化的异质性。我们将使用Illumina平台从相关的生物途径中进行基因型单核苷酸多态性（SNP）。将使用补充了以前据报道具有功能意义的SNP的TAGSNP方法来选择候选SNP。此外，深度重新序列将用于识别我们的PILOT数据中与小儿GCT相关的四个基因中的变体，Kitlg，spry4，bak1和dmrt1。我们将使用Illumina Human -Methylation27 Beadchip评估基因组宽的DNA甲基化，这将使我们能够选择GCT特征的CpG位点。该应用中提出的研究很重要，因为它将是迄今为止儿科GCT的最大遗传流行病学研究，它将评估与遗传易感性有关的新型关联。此外，了解小儿GCT中的甲基化模式可能表明肿瘤的发育阶段。 公共卫生相关性：小儿生殖细胞肿瘤（GCT）是影响每年约360名儿童的癌症；某些小儿GCT的发病率正在上升。对于为什么这些类型的癌症在儿童中发展的原因很少，但是在胎儿发育过程中发生的基本遗传过程中的异常可能起作用。我们提出了有史以来最大的分子流行病学研究，以评估潜在的遗传易感性对小儿GCT发展的贡献。我们的目标是就早期事件如何导致基因功能的长期改变并增加癌症的风险提供重要见解。