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的恶性生殖细胞肿瘤（GCT）被假设为是一种恶性生殖细胞肿瘤。 子宫内事件的结果。成人睾丸GCT（TGCT）的高遗传性提示遗传病因， 最近的全基因组关联研究通过发现多个易感基因座支持了这一点。我们 最近证实了这些基因座的一个子集作为儿童GCT的易感性变体。5年相对生存率 GCT的总体发生率非常高，主要是由于顺铂化疗的有效性， 20%的患者会表现出对化疗的抵抗或治疗后复发。临床危险分层 确定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，可能有助于定制治疗。我们最近完成的儿童肿瘤组（COG）病例- GCT的父母三联体研究是第一个从儿童和青少年中收集生殖系DNA样本的大型研究 GCT病例、肿瘤标本和结局数据。本申请中提出的研究将使我们能够 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的范围， 通过扩大我们对生殖细胞遗传变异的分析，包括性染色体。我们的总目标 这项研究的目的是评估遗传学和表观遗传学在儿科GCT风险中的作用， 结果。我们的假设是，DNA甲基化模式将预测GCT病例谁可能有穷人 结果。此外，我们假设性染色体上常见和中度罕见的变异 增加GCT风险。为了评估这些假设，我们将结合联合收割机的数据，从我们正在进行的COG的情况下，家长 获得了儿童GCT（N=867例病例和1，517例父母对照）与GCT病例和对照的三联研究 来自加州、密歇根州和华盛顿州生物样本库项目（N= 1，601例病例和1，601例对照）。 我们的主要目标将是：1）确定甲基化模式，预测不良结果，包括疾病复发 和死亡，和2）发现单核苷酸多态性（SNP）和拷贝数变异（CNV）上， 性染色体导致儿童和青少年GCT风险。我们还将评估 通过在探索性目的中使用总负荷试验来检测GCT中的罕见遗传变异。甲基化将 使用Illumina EPIC甲基化阵列在500个GCT肿瘤样品中进行评估。种系遗传分析 将使用在Illumina Human CoreExome阵列上生成的现有GWAS数据进行。的 将通过分析生成的全外显子组测序数据评估罕见变异的贡献 通过加布里埃拉米勒儿童第一儿科研究计划（N=250三人组）和外显子组内容可用 整个数据集（N= 2，468例病例）。儿童GCT的病因学知之甚少;生殖细胞分析 遗传变异将为疾病生物学提供线索。鉴定与贫穷相关的甲基化模式 预后可以改善现有的临床危险分层，并提出新的治疗途径。最后， 这将是第一个在任何年龄组中包括非欧洲血统个体的GCT易感性研究。