Custom array CGH for glioma diagnosis and management

描述（由申请人提供）：恶性胶质瘤是常见的原发性人类脑肿瘤，但其病理分类的问题影响了患者的管理。 这些困难引起了人们对分子遗传学方法的极大兴趣。 临床相关的遗传协会已被发现，但实际问题阻碍了广泛的诊断应用这方面的知识。 我们假设自定义阵列比较基因组杂交（aCGH）可以提供一种灵敏，特异，具有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学相关的遗传变化，这种第一代自定义CGH阵列将提供基础，以提高诊断相关性，为未来的检测。 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的现有优势。 对于R21组分，我们将：1）与标准测定相比，评价定制aCGH的灵敏度和特异性; 2）生成CGH的定制BAG阵列，包括提供广泛基因组覆盖以及染色体1、7、9、10、19和X以及其他选择基因座的集中覆盖的靶标。 一旦我们满足了上述R21目标的要求，我们将在R33部分中进行：1）评估如aCGH所揭示的所测定的染色体上特定区域的改变是否在两个仔细注释的恶性胶质瘤患者队列中提供与化学反应和存活的改善的和/或新的相关性：a）间变性少突胶质瘤患者的回顾性系列;和B）恶性神经胶质瘤患者的前瞻性系列。 然后，我们将：2）使用来自R33目标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检测方法来检测恶性胶质瘤中各种临床病理学相关的遗传改变。 我们还预计，这些信息将有助于确定关键的胶质瘤基因，以及建设下一代诊断方法。 鉴于这些终点，该应用程序对PA-04-102“癌症预后和预测阶段性应用奖”具有高度响应性。"

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."