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 神经胶质瘤的治疗2016年夏天，世界卫生组织（WHO）发布了最新诊断结果。 包括分子标记物在内的神经胶质瘤标准，迈出了分子精确诊断的第一步。是 我们的长期目标是利用脑肿瘤库的纵向资源， 胶质瘤预后和治疗假设。在亨利福特的240例病例中， 癌症基因组图谱（The Cancer Genome Atlas）开始了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的临床注释脑肿瘤库，我们将专注于治疗 结果，复发性疾病和延长生存期，这些都没有在TCGA项目中获得。对于这项工作， 我们已经建立了一个跨学科的合作者团队，具有临床和信息学专业知识， 另外340例神经胶质瘤病例（WHO II-IV级）。我们总共将评估700份肿瘤标本（FFPE/冷冻） 来自HFH肿瘤库（2001年至今），代表原发性和匹配的进展性疾病（目标1）。 将通过外显子组测序生成分子数据，以评估DNA序列和拷贝数变体， 靶向桑格测序来分析TERT启动子，DNA甲基化阵列分析来分析 甲基化我们的肿瘤库的临床注释，包括长期随访和治疗方案，将 添加到550个神经胶质瘤病例中。由此产生的全面注释的肿瘤库将是 提供临床分子关联和疾病进展查询的宝贵资源 给HFH和其他地方的研究人员在这个建议中，我们使用我们的数据库来解决两个分析目标：（Aim 2)仔细设计现代诊断类别中预后和治疗反应的统计模型 使用回顾性记录;（目的3）确定每个患者在治疗过程中出现的基因组差异 治疗和进展，我们预计这将影响治疗决策，并告知标准治疗 战略布局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 生存率异常，这可能表明差异分子诊断或建议治疗途径， 在别人身上延续生命。

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.