Post genome wide association studies in testicular germ cell tumors

睾丸生殖细胞肿瘤的全基因组关联研究

• 批准号: 10478194
• 负责人: PETER A KANETSKY
• 金额: $ 142.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478194
• 关键词: Accounting; Address; Adult; Affect; Age; Biological; Biology; Brothers; CHEK2 gene; Candidate Disease Gene; Chromosome abnormality; Cisplatin; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Common Neoplasm; Copy Number Polymorphism; Custom; DNA Maintenance; Data; Data Set; Development; Developmental Cell Biology; Disease; Disease susceptibility; Environmental Risk Factor; Epidemiology; European; Evaluation; Fathers; Genes; Genetic Predisposition to Disease; Genetic Variation; Genomic Instability; Genotype; Genotype-Tissue Expression Project; Germ Cells; Goals; Heritability; Incidence; Individual; Infertility; Inherited; International; Investigation; Kinetochores; Male Infertility; Malignant Neoplasms; Malignant neoplasm of testis; Medicine; Morbidity - disease rate; Morphology; Pathway interactions; Patients; Penetrance; Platinum; Predisposition; RNA Splicing; Research; Resources; Risk; Risk Marker; Role; Site; Small Interfering RNA; Somatic Cell; Source; Spermatocytes; Statistical Models; Survivors; Susceptibility Gene; Testicular Germ Cell Tumor; Time; Tumor Cell Biology; Tumor Cell Line; Validation; Variant; Work; aged; base; biobank; cancer type; causal variant; chemotherapy; cohesion; disorder risk; exome; exome sequencing; fetal; genetic association; genetic epidemiology; genome wide association study; genome-wide; genomic locus; heterogenous data; high risk; high risk men; improved; in silico; in vitro Model; insight; knock-down; long-term sequelae; member; men; novel; overexpression; rare variant; segregation; sex determination; single cell sequencing; success; transcriptome; young man

The Testicular Cancer Consortium (TECAC) is the only international collaborative group whose goal is to understand the genetic susceptibility to testicular germ cell tumors (TGCT). The incidence of TGCT is highest among men of European ancestry, and the most common cancer affecting men aged 15-45. TECAC and its members have conducted successful genome-wide association studies (GWAS) of TGCT; our latest analysis has identified 22 novel susceptibility alleles bringing the total validated risk markers to 68, accounting for 43% of heritability. Our studies have revealed the critical role of variation affecting essential pathways of male germ cell development and maturation, sex determination, chromosomal segregation, and DNA maintenance in TGCT susceptibility. We propose three complementary aims to deepen our discovery of inherited variation of susceptibility to TGCT, results of which will refine our understanding of the biology of TGCT and male germ cell development, provide insights into inherited variation predisposing to genomic instability, and improve our ability to identify patients at highest risk of disease. In Aim 1, we will identify rare and common variants (individual and gene burden) using whole exome (WES) approaches followed by independent validation. We will conduct de novo WES on extant biosamples from 1000 and 1000 men with and without TGCT, respectively, and assemble existing WES data from 2066 men with TGCT from TECAC members for comparison to genomically matched (1:4) unaffected men from the Penn Medicine and UK Biobanks. To address data heterogeneity, WES data from all sources will be called together using a common pipeline. Fifty genes and 500 SNPs will be selected for validation in an independent set of extant biosamples from 5000 and 5000 men with and without TGCT, respectively, all with existing genome-wide genotyping. In Aim 2, we will conduct a transcriptome-wide association study (TWAS), preceded by the largest GWAS study to date in 15,847 men with TGCT and 27,178 (230,610 with deCODE) men without TGCT. We will use a customized version of FUSION to perform the TWAS, annotated with expression data derived from TGCT cell lines, fetal and adult germ cells, GTEx, and single cell sequencing of germ cells. In Aim 3, after in silico assessment and prioritization, 20 top loci/genes will be evaluated in TGCT in vitro models using siRNA and CRISPR to assess over-expression and knockdown effects on morphology, proliferation, chromosomal abnormalities, and cisplatin sensitivity. We will select candidate genes from our past genetic association efforts (11 preliminarily prioritized) and from novel loci/genes found in our WES (Aim 1), GWAS and TWAS (Aim 2) efforts. Our renewal builds upon our accomplishments and paves the way to identify novel susceptibility loci through three highly cohesive aims. Our findings will lead to further ground-breaking insights into the biology and genetic etiology of TGCT and will provide data needed to identify men at greatest need for surveillance, the optimal way to decrease serious TGCT treatment-related morbidity.

睾丸癌症联合会(TECAC)是唯一一个其目标是 了解睾丸生殖细胞肿瘤(TGCT)的遗传易感性。TGCT的发病率最高 在欧洲血统的男性中，是最常见的癌症，影响15-45岁的男性。TECAC及其ITS 成员已经成功地进行了TGCT的全基因组关联研究；我们的最新分析 已确定22个新的易感等位基因，使已验证的风险标记总数达到68个，占43% 遗传能力的问题。我们的研究揭示了影响雄性生殖细胞基本途径的变异的关键作用 细胞发育和成熟、性别决定、染色体分离和DNA维持 TGCT敏感性。我们提出了三个相辅相成的目标，以深化我们对遗传变异的发现 TGCT的易感性，其结果将加深我们对TGCT和男性生殖细胞生物学的理解 发展，提供对易导致基因组不稳定的遗传变异的洞察，并改善我们的 能够识别疾病风险最高的患者。在目标1中，我们将识别罕见和常见的变体 (个体和基因负担)使用完整外显子组(WES)方法，然后进行独立验证。我们 将对1000名和1000名男性的现有生物样本进行新的WES， 并收集来自TECAC成员的2066名患有TGCT的男性的现有WES数据 与来自宾夕法尼亚医学和英国生物库的基因匹配(1：4)的未受影响的男性进行比较。至 为了解决数据异构性，所有来源的WES数据将使用公共管道调用在一起。五十 基因和500个SNP将被选为在5000个和500个现有生物样本中进行验证的独立集合 分别有5000名患有TGCT和没有TGCT的男性，他们都有现有的全基因组基因分型。在目标2中，我们将 进行转录组范围的关联研究(TWAS)，在此之前进行了迄今为止规模最大的 15,847名患有TGCT的男性和27,178名(230,610名患有脱码)男性没有TGCT。我们将使用定制的 融合的版本以执行TWAS，用来自TGCT细胞系的表达数据注释，胎儿 和成体生殖细胞、GTEx和生殖细胞的单细胞测序。在目标3中，在硅胶评估和 优先顺序，20个顶级基因座/基因将在TGCT体外模型中使用siRNA和CRISPR进行评估 过度表达和基因敲除对形态、增殖、染色体异常和 顺铂敏感性。我们将从我们过去的遗传关联努力中选择候选基因(初步为11个 优先)和在我们的WES(目标1)、GWAS和TWAS(目标2)工作中发现的新的基因座/基因。我们的 更新建立在我们的成就基础上，并为通过三个新的易感基因座识别新的易感基因座铺平了道路 高度一致的目标。我们的发现将导致对生物学和遗传学的进一步开创性的洞察 TGCT的病因学，并将提供必要的数据，以确定最需要监测的男性，最佳 减少TGCT治疗相关严重并发症的方法。