Mechanisms and Fetal Origins Underlying Gonadal Germ Cell Tumor-AWARDED

项目摘要 睾丸生殖细胞肿瘤（TGCT）是15-45岁男性最常见的癌症， 癌症导致最大的寿命损失。患有性腺/生殖器发育不良的儿童（申请人的 生殖细胞肿瘤的发病率是男性生殖细胞肿瘤发病率的50%。然而，哪些基因易患这些疾病？ 肿瘤，因此将成为基于精确医学的预防和治疗方法的目标， 大部分是未知的。申请人最近鉴定了第一个诱发TGCT的孟德尔基因， 新的TGCT全基因组关联命中。在这里提出的研究项目中，我们将确定 这些基因组变异损害细胞自主生殖细胞特化的机制和/或 表观遗传重编程（Aim 1）和性腺生态位形成（Aim 2）。我假设等位基因 易患TGCT损害生殖细胞发育的特定阶段。这些目标将通过使用 人类生殖细胞与诱导多能干细胞（iPSC）的创新建模，以及 ~ 100，000名儿童，具有表型数据，可用于识别性腺/生殖器发育不良和 TGCT。这些数据将促进我们对TGCT易感性和启动的理解，并将扩大我们的研究范围。 了解典型的性腺发育。本研究的结果将为未来的精密度提供依据 癌症预防和治疗策略。该提案描述了申请人的五年计划， 作为一名专注于生殖细胞肿瘤的学术肿瘤遗传学家，发展独立的研究生涯 易感性和预防。申请人派尔博士是儿童医院的儿科遗传学家 费城（CHOP）的基础分子生物学和精准医学博士培训。她的研究 重点是识别易患TGCT的生殖系遗传特征，并了解其 行动机制。该奖项的目标是进一步发展成功职业生涯所需的技能 作为一名独立的调查员，包括生物信息学分析和处理大型遗传和 表型数据集，用iPSC对人体组织建模，以及癌症生物学。这个奖项的导师， Drs. Hakon Hakonarson和凯瑟琳L. Nathanson是国际公认的儿科领域的领导者 基因发现和癌症的遗传易感性。派尔博士将得到一名 导师委员会由肿瘤学，统计遗传学和性腺发育的领导者组成。派尔医生 也将受益于无与伦比的资源和指导，可在CHOP和大学 宾夕法尼亚

PROJECT SUMMARY Testicular germ cell tumor (TGCT) is the most common cancer in men 15-45 years old, and among adult cancers results in the greatest years of life lost. Among children with gonadal/genital atypia (the applicant’s specialty), the lifetime risk of gonadal germ cell tumor is up to 50%. However, which genes predispose to these tumors, and thus would be targets for precision-medicine-based prevention and treatment approaches, remain mostly unknown. The applicant recently identified both the first Mendelian gene predisposing to TGCT, and new genome-wide association hits for TGCT. In the research project proposed here we will determine the mechanisms through which these genomic variations impair cell-autonomous germ cell specification and/or epigenetic reprogramming (Aim 1) and gonadal niche formation (Aim 2). I hypothesize that alleles which predispose to TGCT impair specific stages of germ cell development. These aims will be accomplished using innovative modeling of human germ cells with induced pluripotent stem cells (iPSCs), and a genetic biobank of ~100,000 children with phenotypic data by which to identify those with gonadal/genital atypia and risk for TGCT. This data will advance our understanding of TGCT predisposition and initiation, and will expand our knowledge of typical gonadal development. The results from this study will provide rationale for future precision cancer prevention and treatment strategies. This proposal describes a five-year plan for the applicant to develop an independent research career as an academic oncogeneticist focused on germ cell tumor predisposition and prevention. The applicant, Dr. Pyle, is an attending pediatric geneticist at Children’s Hospital of Philadelphia (CHOP) with PhD training in basic molecular biology and precision medicine. Her research focuses on identifying germline genetic features that predispose to TGCT, and understanding their mechanisms of action. The goals for this award are to further develop the skills required for a successful career as an independent investigator, including expertise in bioinformatic analysis and handling of large genetic and phenotypic data sets, modeling of human tissue with iPSCs, and cancer biology. The mentors for this award, Drs. Hakon Hakonarson and Katherine L. Nathanson, are internationally recognized leaders in pediatric genetic discovery and genetic predisposition to cancer, respectively. Dr. Pyle will be supported by a mentorship committee comprising leaders in oncology, statistical genetics, and gonadal development. Dr. Pyle will also benefit from the unparalleled resources and mentorship available at CHOP and the University of Pennsylvania.