Molecular and clinical evaluation of the glioma patient experience to anticipate modern outcomes and guide patient care

项目摘要 我们和其他人最近发表的里程碑式的论文标志着分子诊断和精确度的新时代 治疗神经胶质瘤。2016年夏天，世界卫生组织(WHO)发布了最新的诊断 包括分子标志物的胶质瘤标准，朝着分子精确诊断迈出了第一步。它是 我们的长期目标是利用脑瘤库的纵向资源来快速评估分子 脑胶质瘤预后和治疗的假说。由于亨利·福特的240起案件的重大贡献 医院(HfH)，由癌症基因组图谱发起了一项对胶质瘤进行分子和临床分析的努力 (TCGA)项目。利用我们在HfH的临床注释脑肿瘤数据库，我们将专注于治疗 预后、复发疾病和延长生存期，这些都没有被纳入TCGA项目。对于这项工作， 我们已经建立了一个由具有临床和信息学专业知识的合作者组成的跨学科团队，以分析 另有340例胶质瘤病例(WHO II-IV级)。总共，我们将评估700个肿瘤标本(FFPE/冰冻) 来自HFH肿瘤库(2001年至今)，代表原发和匹配的进展性疾病(目标1)。 分子数据将通过外显子组测序产生，以评估DNA序列和拷贝数变体， 靶向Sanger测序分析TERT启动子，DNA甲基化阵列分析 甲基组。来自我们肿瘤库的临床注释，包括长期随访和治疗方案，将是 添加到550个有侧写的神经胶质瘤病例中。由此产生的全面注释的肿瘤库将是一个 为查询临床-分子关联和疾病进展提供了宝贵的资源 给HFH和其他地方的研究人员。在本提案中，我们使用我们的数据库来解决两个分析目标：(AIM 2)精心设计现代诊断类别间预后和治疗反应的统计模型 使用回顾记录；(目标3)确定每个患者在治疗过程中产生的基因组差异 治疗和进展，我们预计这将影响治疗决定，并为标准治疗提供信息 战略。作为第三个目标的一部分，我们还将探索患者的基因组模式和临床反应 具有特殊的存活率，这可能表明鉴别的分子诊断或建议的治疗途径 延长其他人的生存时间。

Project Summary Landmark papers published recently by us, and others, mark the new era of molecular diagnoses and precision therapy for glioma. In the summer of 2016, the World Health Organization (WHO) published updated diagnosis criteria for glioma that include molecular markers, taking a first step toward a molecularly precise diagnosis. It is our long-term goal to capitalize on the longitudinal resources of brain tumor banks to rapidly assess molecular hypotheses for prognosis and treatment of glioma. With the significant contribution of 240 cases from Henry Ford Hospital (HFH), an effort to molecularly and clinically profile glioma was started by The Cancer Genome Atlas (TCGA) project. Capitalizing on our clinically annotated brain tumor bank at HFH, we will focus on therapeutic outcomes, recurrent disease, and extended survival, which were not captured in the TCGA project. For this work, we have constructed an interdisciplinary team of collaborators, with clinical and informatics expertise, to profile an additional 340 glioma cases (WHO grade II-IV). In total, we will assess 700 tumor specimens (FFPE/frozen) from the HFH tumor bank (2001-present), representing both primary and matched progressive disease (Aim 1). Molecular data will be generated by exome sequencing to assess DNA sequence and copy number variants, targeted Sanger sequencing to profile the TERT promoter, and DNA methylation array assays to profile the methylome. Clinical annotation from our tumor bank, including long-term follow-up and therapy regimens, will be added to each of the 550 profiled glioma cases. The resulting comprehensively-annotated tumor bank will be an invaluable resource for queries of clinical-molecular associations and the progression of disease, made available to researchers at HFH and beyond. In this proposal we use our database to address two analytical aims: (Aim 2) to carefully design statistical models of prognosis and therapy response among modern diagnosis classes using retrospective records; (Aim 3) to identify genomic differences, per patient, arising over the course of treatment and progression, which we expect will impact therapy decisions and inform standard treatments strategies. As part of the third aim, we will also explore the genomic patterns and clinical response of patients with exceptional survival, which may indicate differential molecular diagnosis or suggest therapeutic avenues for extending survival in others.