The Use of a Zebrafish Germ Cell Tumor Mutant to Identify Putative Genetic Mutation Drivers in Human Testicular Germ Cells Tumors

使用斑马鱼生殖细胞肿瘤突变体来识别人类睾丸生殖细胞肿瘤中假定的基因突变驱动因素

• 批准号: 9211685
• 负责人: KELLEE R SIEGFRIED
• 金额: $ 9.61万
• 依托单位: UNIVERSITY OF MASSACHUSETTS BOSTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9211685
• 关键词: Adverse effects; Affect; Aftercare; Age; Age-Years; Animal Model; Animals; Area; Basic Science; Boston; Cancer Center; Cancer Research Project; Candidate Disease Gene; Classification; Collaborations; Collection; DNA Sequence Alteration; Dana-Farber Cancer Institute; Data; Development; Diagnostic Neoplasm Staging; Disease; Faculty; Fishes; Genes; Genetic; Genomics; Germ Cells; Germ cell tumor; Goals; Human; Incidence; Knowledge; Lead; Lesion; Life; Malignant Neoplasms; Massachusetts; Modeling; Molecular; Molecular Genetics; Mutate; Mutation; Names; Oncologist; Pathologist; Pathway interactions; Patients; Phenotype; Pilot Projects; Predisposition; Primary Neoplasm; Quality of life; Research; Research Personnel; Research Support; Resistance; Rodent Model; Sample Size; Sampling; Seminoma; Side; Staging; Techniques; Technology; Testicular Germ Cell Tumor; Testing; Therapeutic Intervention; Translating; Tumor Cell Line; Tumor stage; Tumor-Derived; Underrepresented Students; Universities; Variant; Work; Zebrafish; anticancer research; base; cancer health disparity; cancer type; career development; cost effective; diagnostic biomarker; exome; exome sequencing; experience; gene discovery; genetic analysis; genetic variant; genome sequencing; genomic data; histological studies; human data; human disease; improved; model building; mutant; novel; programs; rare variant; targeted treatment; tumor; tumorigenesis; tumorigenic; underrepresented minority student; whole genome; young man

Summary: Testicular Germ Cell Tumors (TGCTs) are the most common type of cancer affecting younger men between the ages of 20 and 40 years old. TGCTs typically respond well to current treatments, yet about 5% of cases are resistant. Furthermore, current treatments can have many adverse side affects that extend later in life warranting the need for improved, more targeted therapies. However, the genetic and molecular causes of TGCTs are largely unknown. To develop improved treatments for this disease requires a better understanding of the molecular underpinnings of TGCT formation. The aims of the project are to uncover mutations that drive TGCT tumorigenesis and/or increase susceptibility, and identify putative causative variants in human TGCTs through two main approaches: 1) develop an animal model with a high incidence of TGCTs, and 2) genome sequencing of tumor samples derived from patients. TGCTs consist of several subtypes, only one of which has an available mammalian model. Furthermore, TGCT cell lines are notoriously difficult to derive and are therefore largely unavailable. The zebrafish is an excellent animal model for many human diseases, including cancer. Strikingly, two zebrafish mutant lines have been identified that give rise to seminoma-type TGCT, which is the most common TGCT. Studies of these existing mutants identified mutated or misregulated genes in human TGCTs. We identified a novel zebrafish mutant line with a high incidence of TGCTs, named zgt (zebrafish germ cell tumor). This mutant is distinct from known zebrafish TGCT mutants and thus provides novel inroads to discovering molecular mechanisms underlying TGCT formation. To test for drivers of TGCTs in humans, this pilot proposes a genomic sequencing approach of patient samples with the goal of discovering mutations that arise during TGCT formation and thus may drive tumorigenesis. To facilitate identification of rare alleles, the project will use the knowledge gained from studies of our zebrafish model to guide targeted searches for mutations in human patient samples. This approach will facilitate the identification of mutations that may drive tumorigenesis, even with a limited number of primary tumor samples. Through this work, this pilot project will establish a new animal model for TGCT studies that will be used to uncover genetic and mechanistic causes of tumor formation. The project will translate the knowledge gained from the animal model through comparisons with genomic analysis attained from tumors derived from human patients, which will facilitate the identification of potential areas for therapeutic intervention. This project directly relates to the goals of the U54 Partnership as it supports collaborative research between oncologists and pathologists at DF/HCC and a basic science research group at UMass Boston. This collaboration is essential in establishing the project's translational model and building the cancer research program at UMass Boston. Furthermore, this project will provide opportunities for underrepresented minority (URM) students to engage in cancer research, and support career development of early stage investigators.

摘要：睾丸生殖细胞肿瘤(TGCT)是影响年轻男性的最常见的癌症类型 年龄在20岁到40岁之间。TGCT通常对当前的治疗反应良好，但约5% 病例是耐药的。此外，目前的治疗方法可能有许多副作用，这些副作用会在以后延续。 生活证明需要改进的、更有针对性的治疗。然而，遗传和分子原因 TGCT在很大程度上是未知的。要开发这种疾病的改进治疗方法，需要更好地了解 TGCT形成的分子基础。该项目的目标是发现驱动 TGCT在人类TGCT中的肿瘤发生和/或增加易感性，并识别可能的致病变异 通过两个主要途径：1)建立TGCT高发的动物模型；2)基因组 对来自患者的肿瘤样本进行测序。TGCT由几个子类型组成，其中只有一个具有 一个可用的哺乳动物模型。此外，TGCT细胞系是出了名的难以衍生，而且 因此很大程度上是无法获得的。斑马鱼是许多人类疾病的绝佳动物模型，包括 癌症。引人注目的是，已经鉴定出两个斑马鱼突变系，它们会导致精原细胞瘤型TGCT， 这是最常见的TGCT。对这些现有突变体的研究发现了突变或调控错误的基因 在人类TGCT中。我们鉴定了一个新的斑马鱼突变系，命名为zgt，具有高TGCT的发生率。 (斑马鱼生殖细胞瘤)。该突变体不同于已知的斑马鱼TGCT突变体，因此提供了 发现TGCT形成的分子机制的新进展。测试TGCT的驱动程序 在人类中，这项试点提出了一种对患者样本进行基因组测序的方法，目的是发现 在TGCT形成过程中出现的突变，因此可能会推动肿瘤的发生。为方便辨认 稀有等位基因，该项目将使用从斑马鱼模型研究中获得的知识来指导有针对性的 在人类患者样本中搜索突变。这种方法将有助于识别突变。 这可能会推动肿瘤的形成，即使是有限数量的原发肿瘤样本。通过这项工作，这 试点项目将为TGCT研究建立一种新的动物模型，用于揭示遗传和 肿瘤形成的机制原因。该项目将把从动物模型中获得的知识转化为 通过与从人类患者肿瘤中获得的基因组分析进行比较，这将是 促进确定潜在的治疗干预领域。该项目直接与 U54伙伴关系的目标，因为它支持肿瘤学家和病理学家之间的合作研究，网址为 和波士顿大学波士顿分校的一个基础科学研究小组。这种协作对于建立 该项目的翻译模型和在马萨诸塞州大学波士顿分校建立癌症研究计划。此外，这一点 该项目将为代表不足的少数族裔(URM)学生提供从事癌症研究的机会， 并支持早期调查人员的职业发展。