Custom array CGH for glioma diagnosis and management

描述（申请人提供）：恶性胶质瘤是常见的人类原发性脑肿瘤，但其病理分类的问题影响了患者的治疗。这些困难引起了人们对分子遗传学方法的极大兴趣。临床相关的遗传关联已经被发现，但实际问题阻碍了这种知识的广泛诊断应用。我们假设，定制阵列比较基因组杂交（aCGH）可以提供一种敏感、特异性、成本效益和快速的方法来评估人类恶性胶质瘤的各种临床病理相关的遗传变化，并且这种第一代定制CGH阵列将为提高未来检测的诊断相关性提供基础。为了评估这种可能性，我们提出了一个两阶段的计划，利用我们在分子遗传学、病理学、生物统计学和临床数据库方面的现有优势。对于R21组分，我们将：1)与标准测定法相比，评估自定义aCGH的敏感性和特异性；2)为CGH生成定制的BAG阵列，包括提供广泛基因组覆盖的靶标，以及染色体1、7、9、10、19和X以及其他选择位点的集中覆盖。一旦我们达到了上述R21目标的里程碑，我们将继续进行R33部分：1)评估aCGH所揭示的被检测染色体上特定区域的改变是否与两组精心注释的恶性胶质瘤患者的化学反应和生存率提供了改善和/或新的相关性：a)一系列间变性少突胶质细胞瘤患者的回顾性研究；b)一系列恶性胶质瘤患者的前瞻性研究。然后，我们将：2)利用R33的Aim 1的数据开发基于acgh的恶性胶质瘤分类。该项目的长期目标是实施一种实用的分子测定方法，以检测恶性胶质瘤中各种临床病理相关的遗传改变。我们也期望这些信息将有助于关键胶质瘤基因的鉴定以及下一代诊断方法的构建。考虑到这些终点，该应用对PA-04-102有很高的反应，“癌症预后和预测的分期应用奖”。

DESCRIPTION (provided by applicant): Malignant gliomas are common primary human brain tumors, but problems in their pathological classification compromise patient management. These difficulties have sparked considerable interest in molecular genetic approaches. Clinically relevant genetic associations have been discovered, but practical problems have prevented widespread diagnostic application of this knowledge. We hypothesize that custom array comparative genomic hybridization (aCGH) could provide a sensitive, specific, cost-effective and rapid method to assess human malignant gliomas for a variety of clinicopathologically relevant genetic changes and that such first-generation custom CGH arrays will provide the basis for improving diagnostic correlations for future assays. To evaluate this possibility, we propose a two-stage plan that capitalizes on our existing strengths in molecular genetics, pathology, biostatistics and clinical databases. For the R21 component, we will: 1) evaluate custom aCGH sensitivity and specificity in comparison to standard assays; and 2) generate custom BAG arrays for CGH that include targets providing broad genomic coverage as well as focused coverage of chromosomes 1, 7, 9, 10, 19 and X, and other select loci. Once we have met the Milestones from the above R21 Aims, we will proceed in the R33 component to: 1) evaluate whether alterations of particular regions on the assayed chromosomes, as revealed by aCGH, offer improved and/or novel correlations with chemoresponse and survival in two carefully annotated cohorts of malignant glioma patients: a) a retrospective series of anaplastic oligodendroglioma patients; and b) a prospective series of malignant glioma patients. We will then: 2) develop an aCGH-based classification of malignant gliomas using the data from Aim 1 of the R33. The long-term goal of this project is the implementation of a practical molecular assay to detect a variety of clinicopathologically relevant genetic alterations in malignant gliomas. We also anticipate that such information will contribute to identification of key glioma genes as well as to construction of next-generation diagnostic approaches. Given these endpoints, the application is highly responsive to PA-04-102, "Phased application awards in cancer prognosis and prediction."