GENETIC ALTERATIONS IN MULTIFOCAL PRIMARY BRAIN TUMORS

我们已经注意到，近10年前罕见的多灶性胶质瘤已经 在过去的几年里，这种情况的发生频率急剧增加。 此外，我们发现患者继发恶性肿瘤的发生率增加。 多灶性疾病表明可能存在基因异常。 最近的证据表明，两个负增长的异常 调控基因，神经纤维瘤病1型(NF1)和P53基因，以及 正向生长调节基因--表皮生长因子受体 表皮生长因子受体(EGFR)基因可能参与了恶性脑的发生发展 肿瘤。这个项目的第一个目标是研究不同的 P53、NF1和EGFR基因以及胚系53的体细胞变化 多灶性和单灶性胶质瘤患者的基因突变 患有第二种恶性肿瘤或有很强的癌症家族史。在……里面 此外，来自多灶性胶质瘤的肿瘤组织将从 以防两个不同的部位和来自第二恶性肿瘤的检查 多灶性胶质瘤形成的单克隆性与多克隆性起源。 生殖系突变患者的家属也将接受检测 并提供遗传咨询。我们的团队发现NF1基因 在GAP中有两种不同类型的成绩单(类型I和类型II) 相关域(GRD)，其差异表达可能是 功能上参与神经外胚层细胞的分化。 第二个目标是检验差异的假设 I型和II型转录本的表达与 患者的恶性肿瘤、多灶性和继发肿瘤的发生率 与恶性胶质瘤有关。最近描述了一种方法，该方法 允许识别不同细胞中不同表达的基因 利用聚合酶链式反应进行分离克隆 单个mRNAs。该项目的第三个目标是应用 这项研究其他未知致癌基因存在的技术 或在这个独特的亚群中通过手术移除的抑制基因 多灶性胶质瘤、与第二种恶性肿瘤相关的胶质瘤和 有强烈家族癌症病史的患者中的胶质瘤。这项研究将 加深对P53、NF1和EGFR基因含义的理解 在神经外胚层的恶变和进展中可能 提供信息以帮助识别有风险的家庭成员 恶性肿瘤的发展。此外，预计未知的 然而，癌基因和抑癌基因将被发现，而 导致或促成肿瘤转化的累积事件 已阐明的神经组织。这项研究的结果可能会打开新的 试图用基因逆转恶性表型的途径 操纵。

We have noticed that multifocal glioma, a rarity almost 10 years ago, has been increased dramatically in frequency over the last few years. Moreover, we found increased incidence of second malignancies in patients with multifocal disease indicating possible genetic abnormalities. Recent evidence suggests that abnormalities of two negative-growth regulatory genes, the neurofibromatosis type 1 (NF1) and p53 genes, and the positive-growth regulatory gene, epidermal growth factor receptor gene (EGFR), may be involved in the development of malignant brain tumors. The first aim of this project is designed to examine the diverse somatic alterations of p53, NF1,and EGFR genes as well as germ line 53 gene mutations in patients with multifocal gliomas and unifocal gliomas with either second malignancies or strong family history of cancer. In addition, tumor tissue from multifocal gliomas will be examined from at lest two different sites and from second malignancies in order to examine the monoclonal versus polyclonal origin of multifocal glioma formation. Family members of patients with germline mutations will also be tested and offered genetic counseling. Our group has found that the NF1 gene has two different types of transcripts (type I and type II) in the GAP related domain (GRD), the differential expression of which might be functionally involved in the differentiation of neuroectodermal cells. The second aim is directed at testing the hypothesis that differential expression of type I and type II transcripts is correlated with the malignancy, multifocality, and incidence of second tumors in patients with malignant gliomas. Recently, a method has been described that allows the identification of differently expressed genes in various cells using the polymerase chain reaction in order to separate and clone individual mRNAs. The third aim of this project is the application of this technique to investigate the presence of other unknown yet oncogenes or suppressor genes in this unique subgroup of surgically removed multifocal gliomas, gliomas associated with second malignancies and gliomas in patients with strong familial cancer history. This study will improve our understanding of the implication of p53, NF1, and EGFR genes in the neuroectodermal malignant transformation and progression and may yield information to help in identifying family members at risk for development of malignancies. Furthermore, it is expected that unknown yet oncogenes and suppressor genes will be discovered, and the accumulated events leading or contributing to neoplastic transformation of the neural tissue elucidated. Results of this study could open new avenues in attempts to reverse the malignant phenotype with genetic manipulation.