Genetics and epigenetics of pediatric germ cell tumors

儿童生殖细胞肿瘤的遗传学和表观遗传学

• 批准号: 10364222
• 负责人: Jenny N. Poynter
• 金额: $ 35.46万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364222
• 关键词: Accounting; Adolescent; Adult; Affect; Age; Biological; Biology; California; Cancer-Predisposing Gene; Cell Line; Cessation of life; Child; Childhood; Childhood Germ Cell Tumor; Cisplatin; Clinical Trials; Complex; Copy Number Polymorphism; Cytotoxic Chemotherapy; DNA; DNA Methylation; Data; Data Set; Development; Diagnosis; Disease; Effectiveness; Embryo; Epigenetic Process; Etiology; Event; Female; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Germ Cell Cancers; Germ Lines; Germ cell tumor; Goals; Heritability; Histology; Human; Individual; Klinefelter' s Syndrome; Knowledge; Lead; Light; Malignant Neoplasms; Methods; Methylation; Michigan; Modification; Molecular; Molecular Analysis; Nucleic Acid Regulatory Sequences; Operative Surgical Procedures; Outcome; Parents; Patients; Pediatric Neoplasm; Pediatric Oncology Group; Pediatric Research; Platinum; Predisposition; Prognosis; Prognostic Factor; Recurrent disease; Relapse; Research; Resistance; Risk; Risk Factors; Role; Sampling; Sex Chromosomes; Single Nucleotide Polymorphism; Solid Neoplasm; Specimen; Survival Rate; Susceptibility Gene; Syndrome; Testicular Germ Cell Tumor; Testing; Treatment Protocols; Triad Acrylic Resin; Turner' s Syndrome; United States; Variant; Washington; Work; X Chromosome; age group; base; biobank; cancer type; case control; chemotherapy; clinical predictors; clinical risk; disease classification; disorder subtype; exome; exome sequencing; genetic analysis; genetic architecture; genetic variant; genome sequencing; genome wide association study; improved; improved outcome; in utero; individualized medicine; insight; large datasets; men; methylation pattern; novel; novel therapeutics; outcome prediction; patient subsets; personalized medicine; programs; public health relevance; rare variant; risk stratification; side effect; tool; trait; tumor; tumor DNA; whole genome; young adult

Scientific Abstract Malignant germ cell tumors (GCTs) in children and adults are hypothesized to occur as a result of events in utero. The high heritability of adult testicular GCT (TGCT) suggests a genetic etiology, and recent genomewide association studies support this through the discovery of multiple susceptibility loci. We recently confirmed a subset of these loci as susceptibility variants for pediatric GCT. While 5-year relative survival rates are very high overall for GCTs, mainly due to the effectiveness of cisplatin chemotherapy, approximately 20% of patients will display resistance to chemotherapy or relapse following treatment. Clinical risk stratification to identify patients with poor prognosis is still very crude and further molecular analysis, including analysis of tumor epigenetics, may help to tailor treatment. Our recently completed Children’s Oncology Group (COG) case- parent triad study of GCT was the first large study to collect germline DNA samples from pediatric and adolescent GCT cases, tumor specimens and outcomes data. The research proposed in this application will allow us to extend the scope of our ongoing study by evaluating tumor DNA methylation as a prognostic factor for GCT and by expanding our analyses of germline genetic variation to include the sex chromosomes. Our overarching goal for the proposed study is to evaluate the contribution of genetics and epigenetics in pediatric GCT risk and outcomes. Our hypothesis is that DNA methylation patterns will predict GCT cases who are likely to have poor outcomes. Further, we hypothesize that common and moderately rare variants on the sex chromosomes increase risk for GCT. To evaluate these hypotheses, we will combine data from our ongoing COG case-parent triad study of pediatric GCT (N=867 cases and 1,517 parent controls) with GCT cases and controls obtained from the state biobank programs in California, Michigan and Washington (N=1,601 cases and 1,601 controls). Our primary aims will be to: 1) Identify methylation patterns that predict poor outcomes, including disease relapse and death, and 2) Discover single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) on the sex chromosomes that contribute to GCT risk in children and adolescents. We will also evaluate the contribution of rare genetic variants in GCT through the use of aggregate burden tests in an exploratory aim. Methylation will be evaluated using the Illumina EPIC methylation array in 500 GCT tumor samples. Germline genetic analyses will be conducted using existing GWAS data generated on the Illumina Human CoreExome array. The contribution of rare variants will be assessed through analysis of whole exome sequencing data generated through the Gabriella Miller Kids First Pediatric Research Program (N=250 trios) and Exome content available for the entire dataset (N=2,468 cases). Little is known about the etiology of pediatric GCT; analysis of germline genetic variation will shed light on disease biology. Identification of methylation patterns associated with poor prognosis could improve the existing clinical risk stratification and suggest new avenues for treatment. Finally, this will be the first study of GCT susceptibility in any age group to include individuals of non-European ancestry.

科学摘要 儿童和成人恶性生殖细胞肿瘤（GCT）作为一种常见疾病竞相发生。 子宫内事件的结果 成人睾丸 GCT (TGCT) 的高遗传力表明有遗传病因，并且 最近的全基因组关联研究通过发现多个易感性位点支持了这一点。 最近证实这些位点的一个子集是儿科 GCT 的易感性变异，同时 5 年相对生存率也较高。 GCT 的总体发生率非常高，主要是由于顺铂化疗的有效性，大约 20% 的患者会出现化疗耐药或治疗后复发。 识别预后不良的患者仍然非常粗略，需要进一步的分子分析，包括分析 肿瘤表观遗传学，可能有助于制定治疗方案，我们最近完成的儿童肿瘤学组 (COG) 案例 - GCT 的父母三联体研究是第一个从儿童和青少年收集种系 DNA 样本的大型研究 本申请中提出的 GCT 病例、肿瘤标本和结果数据将使我们能够 通过评估肿瘤 DNA 甲基化作为 GCT 的预后因素来扩展我们正在进行的研究范围 通过我们对种系遗传变异的分析扩展到包括性染色体。 拟议的研究旨在评估遗传学和表观遗传学在儿科 GCT 风险中的贡献，以及 我们的假设是 DNA 甲基化模式将预测 GCT 病例的情况可能较差。 此外，我们还追踪了性染色体上常见和中等罕见的变异。 为了评估这些假设，我们将结合我们正在进行的 COG 病例母体的数据。 儿科 GCT 三联研究（N=867 例和 1,517 名家长对照），获得 GCT 病例和对照 来自加利福尼亚州、密歇根州和华盛顿州的州生物库计划（N = 1,601 例病例和 1,601 例对照）。 我们的主要目标是：1）确定预测不良结果（包括疾病复发）的甲基化模式 和死亡，以及 2) 发现单核苷酸多态性 (SNP) 和拷贝数变异 (CNV) 我们还将评估导致儿童和青少年 GCT 风险的性染色体。 通过使用总负荷测试来探索 GCT 中的罕见遗传变异。 使用 Illumina EPIC 甲基化芯片对 500 个 GCT 肿瘤样本进行评估。 将使用 Illumina Human CoreExome 阵列上生成的现有 GWAS 数据进行。 将通过分析生成的全外显子组测序数据来评估罕见变异的贡献 通过 Gabriella Miller Kids First 儿科研究计划（N=250 三人组）和可用的外显子组内容 对于整个数据集（N=2,468 例），对儿科 GCT 的病因学分析知之甚少； 遗传变异将揭示与不良相关的甲基化模式的识别。 预后可以改善现有的临床风险分层并提出新的治疗途径。 这将是第一项针对任何年龄组的 GCT 易感性研究，其中包括非欧洲血统的个体。