GENETIC AND BIOLOGIC STUDIES OF 1P AND 19Q IN GLIOMAS

染色体1和19的改变在人脑胶质瘤中是常见的事件，最近被认为与间变性少突胶质瘤的化疗反应和延长生存期有关。然而，这些染色体臂上的基因在胶质瘤中被改变，并可能与化疗反应和生存相关，目前还没有确定。此外，令人兴奋的反应和生存数据还没有在经过适当治疗的前瞻性收集的患者队列中得到证实，这些临床相关性也没有被转化为较低级别的少突胶质细胞瘤或其他神经胶质瘤。我们已经在定位19q基因的基因组位置方面取得了相当大的进展，并在该区域鉴定了几个基因。此外，我们还收集了几个前瞻性收集的患者队列，以证实和扩大凯姆克罗斯等人的临床观察。在这一应用中，我们建议1)完成与胶质瘤发展有关的19q基因的鉴定，2)开始评估19q基因(或多个基因)的功能，3)精细定位胶质瘤中最小的1p缺失区，开始识别与胶质瘤发展有关的1p上的一个或多个基因，以及4)进行临床-翻译研究，旨在验证1p/19q改变的假定预测价值，确定所涉及的特定基因的改变是否具有类似的相关性，并将这种相关性扩展到较低级别的肿瘤和不同胶质细胞谱系的肿瘤。因此，本项目将鉴定并开始研究19q基因的功能，定位1p缺失区，并进一步确定1p和19q突变的临床意义。该项目的总体结果将是对19q和1p基因的遗传学和生物学的初步了解，以及对胶质瘤的联合组织学和基因分型评估的发展，这可能被用于对患者进行治疗。

Alterations of chromosomes 1 and 19 are frequent events in human gliomas and have recently been suggested to be associated with chemotherapeutic response and prolonged survival in anaplastic oligodendrogliomas. However, the genes on these chromosome arms that are altered in gliomas and potentially associated with chemotherapeutic response and survival have not been identified. Furthermore, the exciting response and survival data have not been confirmed in an appropriately-treated, prospectively-collected cohort of patients nor have these clinical correlations been translated to lower grade oligodendrogliomas or other glial tumors. We have made considerable progress in mapping the genomic location of the 19q gene and have identified several genes in this region. In addition, we have assembled several prospectively-collected cohorts of patients to confirm and extend the clinical observations of Caimcross et al. In this application, we propose to 1) Complete the identification of the 19q gene (or genes) involved in the development of gliomas, 2) Begin an evaluation of the function of the 19q gene (or genes), 3) Finely map the minimal 1p deletion region in gliomas, to begin to identify the gene (or genes) on 1p involved in the development of gliomas, and 4) To perform clinical-translational studies designed to validate the postulated predictive value of 1p/19q alterations, to determine if alterations of the specific genes involved have similar associations, and to extend the associations to lower grade tumors and to tumors of different glial lineage. Thus, this project will identify and begin to study the function of the 19q gene, map the 1p deletion region, and further define the clinical significance of the 1p and 19q alterations. The overall result of this project will be an initial understanding of the genetics and biology of the 19q and 1p genes as well as the development of a combined histologic and genotypic assessment of gliomas that could potentially be used to stratify patients for therapy.