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: 9355122
• 负责人: KELLEE R SIEGFRIED
• 金额: $ 9.26万
• 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/9355122
• 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 tests; Disease; Faculty; Fishes; Genes; Genetic; Genomics; Germ Cells; Germ cell tumor; Goals; Human; Incidence; Knowledge; Lead; Lesion; Life; Malignant Neoplasms; Massachusetts; Modeling; Molecular; 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; Techniques; Technology; Testicular Germ Cell Tumor; Testing; Therapeutic Intervention; Translating; Tumor Cell Line; Tumor stage; Tumor-Derived; Tumorigenicity; Underrepresented Students; Universities; Variant; Work; Zebrafish; actionable mutation; anticancer research; cancer health disparity; cancer type; career development; cost effective; diagnostic biomarker; exome; exome sequencing; experience; gene discovery; genetic analysis; genetic predictors; 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癌症类型 年龄在20到40岁之间。TGCT通常对目前的治疗反应良好，但约5%的患者 案件具有抵抗力。此外，目前的治疗可能有许多不良副作用，这些副作用会在治疗后期延长。 这就需要更好的、更有针对性的治疗方法。然而，遗传和分子原因 TGCT在很大程度上未知。为了开发出更好的治疗方法，需要更好地了解 TGCT形成的分子基础该项目的目的是揭示基因突变， TGCT肿瘤发生和/或增加易感性，并鉴定人TGCT中推定的致病变体 通过两种主要方法：1）开发具有高发病率的TGCT的动物模型，和2）基因组 来自患者的肿瘤样品的测序。TGCT由几种亚型组成，其中只有一种具有 一个可用的哺乳动物模型。此外，TGCT细胞系是众所周知的难以衍生的， 因此基本上不可用。斑马鱼是许多人类疾病的极好动物模型，包括 癌引人注目的是，已经鉴定出两种斑马鱼突变系，它们引起了腺瘤型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失调的基因 在人类TGCTs中。我们发现了一种新的斑马鱼突变系，具有高发生率的TGCT，命名为zgt （斑马鱼生殖细胞肿瘤）。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，该试验提出了一种患者样本的基因组测序方法，目的是发现 在TGCT形成过程中出现的突变，因此可能导致肿瘤发生。以便于识别 罕见的等位基因，该项目将利用从我们的斑马鱼模型研究中获得的知识， 在人类患者样本中寻找突变。这种方法将有助于识别突变 这可能会导致肿瘤发生，即使是有限数量的原发性肿瘤样本。通过这项工作， 试点项目将为TGCT研究建立一个新的动物模型，用于揭示遗传和 肿瘤形成的机械原因。该项目将把从动物模型中获得的知识 通过与来自人类患者的肿瘤的基因组分析进行比较， 有助于确定治疗干预的潜在领域。该项目直接关系到 U 54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， DF/HCC和马萨诸塞大学波士顿分校的一个基础科学研究小组。这种合作对于建立 该项目的转化模型和建立癌症研究计划在麻省大学波士顿分校。而且这 该项目将为代表性不足的少数民族（URM）学生提供参与癌症研究的机会， 并支持早期调查人员的职业发展。