Custom array CGH for glioma diagnosis and management

描述(申请人提供)：恶性胶质瘤是常见的原发人类脑肿瘤，但其病理分类的问题影响了患者的治疗。这些困难激起了人们对分子遗传学方法的浓厚兴趣。临床上相关的遗传关联已被发现，但实际问题阻碍了这一知识的广泛诊断应用。我们推测，定制阵列比较基因组杂交(ACGH)可以提供一种敏感、特异、经济有效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基因变化，这种第一代定制CGH阵列将为提高未来分析的诊断相关性提供基础。为了评估这种可能性，我们提出了一个分两个阶段的计划，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成分，我们将：1)与标准检测相比较，评估定制的aCGH的敏感性和特异性；以及2)生成定制的CGH袋阵列，其中包括提供广泛基因组覆盖的靶点，以及对1、7、9、10、19和X染色体以及其他选定基因座的重点覆盖。一旦我们达到了上述R21目标的里程碑，我们将继续进行R33部分的工作：1)评估aCGH揭示的被检测染色体上特定区域的变化是否提供了改善的和/或新的与恶性胶质瘤患者的化疗反应和生存的相关性：a)一系列回顾的间变性少突胶质细胞瘤患者；以及b)一系列预期的恶性胶质瘤患者。然后，我们将：2)使用R33的目标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，以检测恶性胶质瘤中各种临床病理相关的基因变化。我们还预计，这些信息将有助于识别关键的胶质瘤基因，以及构建下一代诊断方法。考虑到这些终点，该应用程序对PA-04-102“癌症预测和预测中的阶段性应用程序奖”具有高度的响应性。

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."