NOVEL BIOMARKERS OF MALIGNANT PROGRESSION IN RECURRENT LOW GRADE GLIOMA

复发性低级别胶质瘤恶性进展的新型生物标志物

• 批准号: 8514310
• 负责人: Susan M Chang
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514310
• 关键词: Accounting; Address; Biological; Biological Markers; Blood Volume; Brain Neoplasms; Cerebrum; Characteristics; Choline; Clinical; DNA Damage; Data; Development; Diagnosis; Diffuse; Diffusion; Evaluation; Evolution; Excision; Exons; Gene Mutation; Genetic; Genome; Genomics; Glioma; Glutamates; Glutamine; Goals; Grant; Histology; Histopathology; Image; Image Analysis; Image-Guided Surgery; Individual; Inositol; Instruction; Knowledge; Lesion; Magnetic Resonance Imaging; Maintenance; Malignant - descriptor; Measures; Methods; Modeling; Molecular Cytogenetics; Mutation; Operative Surgical Procedures; Outcome; Patient Care; Patients; Pattern; Pharmacotherapy; Primary Neoplasm; Principal Investigator; Probability; Property; Radiation therapy; Recording of previous events; Recurrence; Recurrent disease; Recurrent tumor; Relative (related person); Reproduction spores; Role; Sampling; Scanning; Study Subject; Testing; Time; Tissue Sample; Tissues; Tumor Burden; World Health Organization; base; cohort; disease natural history; exome sequencing; genetic evolution; in vivo; indexing; malignant phenotype; neoplastic cell; next generation sequencing; novel; prevent; spectroscopic imaging; treatment effect; treatment strategy; tumor; tumor growth; tumor progression

The goal of the proposed study is to evaluate the role of noninvasive imaging parameters as biomarkers of malignant transformation in diffuse low grade glioma and to use these parameters to select regions for characterizing the genetic mutations associated with recurrent disease. The studies will have a significant impact on the management of these patients by providing objective criteria to predict when a lesion transforms to a more malignant phenotype, whether and where to intervene surgically and how to select the next line therapy. This is an important problem because patients with tumors that recur from a prior LGG have different outcomes depending on histological subtype, grade, and molecular/cytogenetic features. The mechanisms of malignant transformation are unclear and treatment strategies are often pursued without histological confirmation of recurrent tumor. In our previous SPORE Project, we applied magnetic resonance imaging (MRi) and spectroscopic imaging (MRS!) to evaluate 125 patients prior to resection of tumors that were thought to have recurred from a prior LGG. Significant differences in the in vivo MR measures were seen for tumors with malignant transformation compared to those that did not. Ex vivo analysis of the histological status, IDHI mutations and ex-vivo NMR spectra from the image guided tissue samples provided new information that resulted in novel hypotheses being investigated in Specific Aim 1. Extending this approach by defining the mutation profile using next-generation sequencing of image guided tissue samples with defined histology will increase the probability of identifying mutations that drive malignant transformation and address, for the first time, the tumor genome evolution associated with treatment effects and the natural history of the disease.Specific Aim 1 will relate in-vivo MR parameters to malignant transfomriation and clinical outcome and Specific Aim 2 will use paired samples from lesions that either do or do not have the characteristics of malignant transformation, as well as paired samples from the current and subsequent surgery to examine the evolution of the mutation profile. The knowledge gained will make a major impact upon patient care. RELEVANCE (See instructions); This novel project will integrate non-invasive imaging markers that predict malignant transformation with an evaluation of the spatial and temporal patterns of changes in genetic mutations of patients who present with recurrent disease from an original diagnosis of low grade glioma. This will inform on the mechanisms of malignant transformation and will facilitate the development of strategies to prevent or treat the recurrence.

拟议研究的目的是评估非侵入性成像参数作为生物标志物的作用 弥漫性低级别胶质瘤的恶性转化，并使用这些参数来选择区域 表征与复发性疾病相关的基因突变。这些研究将具有重大意义 通过提供客观标准来预测病变何时发生，对这些患者的管理产生影响 转变为更恶性的表型，是否以及在何处进行手术干预以及如何选择 下一线治疗。这是一个重要的问题，因为患有先前 LGG 复发的肿瘤的患者 根据组织学亚型、分级和分子/细胞遗传学特征，有不同的结果。这 恶性转化的机制尚不清楚，治疗策略往往在没有 复发肿瘤的组织学证实。在我们之前的 SPORE 项目中，我们应用了磁共振 成像 (MRI) 和光谱成像 (MRS!) 在肿瘤切除前对 125 名患者进行评估 被认为是从先前的 LGG 中复发的。体内 MR 测量的显着差异是 发生恶变的肿瘤与未发生恶变的肿瘤相比。离体分析 提供的图像引导组织样本的组织学状态、IDHI 突变和离体 NMR 谱 导致新假设的新信息正在具体目标 1 中进行研究。扩展这一点 通过使用图像引导组织样本的下一代测序来定义突变谱的方法 明确的组织学将增加识别驱动恶性转化的突变的可能性 并首次解决了与治疗效果和自然环境相关的肿瘤基因组进化问题 具体目标 1 将体内 MR 参数与恶性转化和 临床结果和具体目标 2 将使用来自具有或不具有以下特征的病变的配对样本 恶性转化的特征，以及当前和后续的配对样本 手术来检查突变谱的演变。所获得的知识将产生重大影响 取决于病人的护理。 相关性（参见说明）； 这个新项目将整合非侵入性成像标记物，以预测恶性转化 评估患有以下疾病的患者基因突变变化的空间和时间模式 最初诊断为低级别胶质瘤而导致的复发性疾病。这将提供有关机制的信息 恶性转化并将促进制定预防或治疗复发的策略。