Genetic Analysis of Chordoma

脊索瘤的遗传分析

• 批准号: 7691580
• 负责人: MICHAEL J KELLEY
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691580
• 关键词: Acceleration; Accounting; Affect; Biology; Bortezomib; Brachyury protein; Cancer Biology; Candidate Disease Gene; Cause of Death; Cell Survival; Cells; Characteristics; Chordoma; Clinical Research; Common Neoplasm; Complement; Decision Making; Diagnosis; Diagnostic Neoplasm Staging; Disease; Dissection; Epigenetic Process; Family; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genomics; Goals; Growth; Health; Healthcare; Healthcare Systems; Hereditary Malignant Neoplasm; Human; Individual; Inherited; Investigation; Laboratories; Link; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Monitor; Mutation; NF-kappa B; Pathogenesis; Pathway interactions; Patients; Play; Process; Relative (related person); Role; Sequence Analysis; Signal Pathway; Signal Transduction; Susceptibility Gene; Syndrome; Therapeutic; Variant; Veterans; Work; base; beta catenin; cancer care; cancer cell; carcinogenesis; cell growth; clinical care; clinical decision-making; clinical practice; design; genetic analysis; genetic variant; improved; in vitro activity; inhibitor/antagonist; insight; knock-down; malignant phenotype; multicatalytic endopeptidase complex; notochord; novel; novel therapeutics; oncology; outcome forecast; response; success; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): In current oncology clinical practice, the histological type and stage of cancer are central determinants of prognosis and treatment decisions. Recently, there has been acceleration in application of molecular predictors to guide clinical decision making with an ultimate goal of individualizing cancer care. However, these molecular predictors have largely been limited to the most common cancers and a few less common cancers that have a well-defined molecular pathogenesis. Yet, uncommon cancers as a group account for about 25% of all malignancies. In this proposal, we propose to complement our ongoing genetic analysis of familial chordoma, a rare cancer thought to arise from notochord, with approaches being applied to individualization of common cancers. The overall goal is to both advance the understanding of pathogenesis of chordoma and guide therapeutic decision making. The successful understanding of the biology of chordoma may provide a roadmap for the study of other rare cancers using analogous approaches and extend individualized cancer care to a broader array of patients. Specific Aim 1. Identify the familial chordoma gene(s). Hypothesis: mutation of a familial chordoma gene(s) predisposes individuals in these families to develop chordoma. Using families with multiple individuals affected with chordoma, my laboratory will identify the familial chordoma gene(s) through sequence analysis and aCGH identification of all genetic variants in the linked region of the largest family. This gene and biochemically-related genes will then be examined in smaller families. Specific Aim 2. Determine the role of brachyury in chordoma cell growth and survival. Hypothesis: brachyury promotes chordoma cell growth and survival, and is a key mediator of chordoma tumorigenesis. Brachyury is a transcription factor that plays a critical role in notochord maintenance, is induced by wnt/beta-catenin signaling, is expressed at high levels in chordoma, and is within the minimal disease gene region for familial chordoma. We will knock-down brachyury in chordoma cells and force its expression in non-chordoma cells followed by assessment of characteristics associated with the malignant phenotype. Specific aim 3. Identify mitogenic pathways altered in chordoma. Hypothesis: Unregulated growth in chordoma is due to dysregulation of specific transcriptional/mitogenic signaling pathways. Leveraging the sensitivity to specific pharmacologic agents, we will dissect growth regulatory signaling pathways in chordoma cells. Based upon growth inhibitory activity in vitro against a chordoma line to the proteosome inhibitor, bortezomib, we will initial focus on defining the transcriptional and signaling pathways altered by this agent. Potential Impact on Veterans Health Care: Although chordoma is a rare tumor, the results of this work will be highly relevant for cancers commonly noted in the Veterans Affairs health care system through better understanding of pathogenesis of malignancy that may establish the basis for improved clinical care. PUBLIC HEALTH RELEVANCE: Cancer is a leading cause of death and suffering. Essentially all human cancers have inherited and/or acquired changes in the genes of cancer cells. Characterizing the changes in genes of cancer cells has been instrumental in recent advances in the clinical care of patients with cancer including improved diagnosis, refinement of prognosis, design of novel therapeutic strategies, and monitoring response to therapy. The identification and characterization of the familial chordoma gene and acquired mutations associated with sporadic (non-familial) chordomas has the potential to increase our understanding of cause(s) of common malignancies.

描述（由申请人提供）： 在当前的肿瘤学临床实践中，癌症的组织学类型和阶段是预后和治疗决策的核心决定因素。最近，分子预测因子在指导临床决策方面的应用加速，其最终目标是个性化癌症护理。但是，这些分子预测因子在很大程度上仅限于最常见的癌症和一些较不常见的分子发病机理的较少常见的癌症。然而，不常见的癌症作为小组占所有恶性肿瘤的25％。在此提案中，我们建议补充我们对家族性综合瘤的持续遗传分析，这是一种罕见的癌症，认为是由诺科德引起的，方法应用于普通癌的个性化。总体目标是既是提高对脊索瘤发病机理的理解，又是指导治疗决策。对Chordoma生物学的成功理解可能为研究其他罕见癌症的研究提供了路线图，并将个性化的癌症护理扩展到更广泛的患者。特定目的1。识别家族性脊髓瘤基因。假设：家族性脊髓瘤基因的突变使这些家族中的个体倾向于发展脊髓瘤。我的实验室使用具有多个患者的家族，将通过序列分析和ACGH鉴定最大家族连接区域的所有遗传变异的家族性脊髓瘤基因。然后将在较小的家庭中检查该基因和生化相关的基因。具体目的2。确定胸瘤在脊髓瘤细胞生长和生存中的作用。假设：Brachyury促进了脊髓瘤细胞的生长和存活，并且是脊髓瘤肿瘤发生的关键介体。 Brachyury是一种转录因子，在脊索维持中起着至关重要的作用，由Wnt/beta-catenin信号传导诱导，在脊索瘤中以高水平表达，并且在家族性脊髓瘤的最小疾病基因区域内。我们将在脊全瘤细胞中敲除胸骨，并迫使其在非双胞胎瘤细胞中的表达，然后评估与恶性表型相关的特征。具体目标3。确定脊髓瘤改变的有丝分裂途径。假设：脊全瘤的不调节生长是由于特定转录/有丝分裂信号通路的失调。利用对特定药理剂的敏感性，我们将剖析脊全瘤细胞中的生长调节信号通路。基于体外对蛋白体抑制剂核糖瘤线硼替佐米的生长抑制活性，我们将最初专注于定义该药物改变的转录和信号通路。对退伍军人卫生保健的潜在影响：尽管脊全瘤是一种罕见的肿瘤，但这项工作的结果将与退伍军人事务医疗系统中常见的癌症高度相关，通过更好地了解恶性肿瘤的发病机理，这可能为改善临床护理提供基础。 公共卫生相关性： 癌症是死亡和痛苦的主要原因。本质上，所有人类癌症都遗传和/或获得了癌细胞基因的变化。表征癌细胞基因的变化在癌症患者的临床护理的最新进展中，包括改善诊断，预后的细化，新型治疗策略的设计以及监测对治疗的反应。家族性脊髓瘤基因的鉴定和表征与偶发的（非家族）脊架有关的突变具有增强我们对普通恶性肿瘤原因的理解的潜力。