Genomic & Genetic Characterization of Amplicons in GBMs

描述(申请人提供)：EGFR、PDGF、INK4a、P53和/或PTEN的改变是恶性胶质瘤中最常见的病变之一。值得注意的是，相当大比例的恶性胶质瘤没有这些标志性的遗传损伤，这意味着许多其他与胶质瘤相关的突变仍然未被识别。功能基因组学的最新进展为快速鉴定和鉴定候选的胶质瘤相关基因及其途径提供了新的能力。利用恶性胶质瘤中与特定基因扩增或缺失相关的复发性染色体改变的存在，基于阵列的CGH技术已经确定了五个高频增益区域。在基因芯片平台上，利用最新优化的基于阵列的CGH，我们将对这五个染色体异常基因进行精细定位和特征分析，以确定最小受累区域内的所有候选基因。辅以各种基于表达的分析，我们将确定CNAs最有可能的体外和体内功能验证靶点。最有潜力的候选胶质瘤癌基因将通过严格的体内转基因研究进一步得到验证。

DESCRIPTION (provided by applicant): Alterations in EGFR, PDGF, INK4a, p53 and/or PTEN are among the most common lesions encountered in malignant gliomas. Notably, a significant proportion of malignant gliomas do not harbor these signature genetic lesions, implying that many other glioma relevant mutations remain unidentified. Recent advances in functional genomics have provided new capabilities for the rapid identification and characterization of candidate glioma-relevant genes and their pathways. Taking advantage of the presence of recurrent chromosomal alterations associated with amplification or deletion of specific genes in malignant gliomas, array-based CGH technique has identified five high-frequency regions of gains. Employing the newly optimized array-based CGH on cDNA microarray platform, we will finely map and characterize these five loci of chromosomal aberrations to identify all candidate genes within the minimal regions of involvement. Complemented with various expression - based analyses, we will identify the most likely targets of CNAs for in vitro and in vivo functional validation. The highest potential candidate glioma oncogene will be further validated by rigorous in vivo transgenesis study.