GENETIC ALTERATIONS IN MULTIFOCAL PRIMARY BRAIN TUMORS

多灶性原发性脑肿瘤的基因改变

• 批准号: 2703022
• 负责人: ATHANASSIOS KYRITSIS
• 金额: $ 9.73万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2703022
• 关键词: brain neoplasms; cell type; epidermal growth factor; family genetics; gene expression; genetic counseling; genetic polymorphism; genetic transcription; glioma; human subject; messenger RNA; neoplasm /cancer genetics; neoplastic transformation; neurofibromatosis; neurogenetics; oncogenes; polymerase chain reaction; regulatory gene; tumor suppressor genes

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.

我们已经注意到，多灶性胶质瘤，一个罕见的近10年前， 在过去的几年里，频率急剧增加。 此外，我们还发现， 多灶性疾病表明可能存在遗传异常 最近的证据表明，两个负增长的异常 调节基因，1型神经纤维瘤病（NF 1）和p53基因，和 正性生长调节基因表皮生长因子受体 EGFR基因可能参与脑恶性肿瘤的发生 肿瘤的 这个项目的第一个目的是研究不同的 p53、NF 1和EGFR基因以及生殖系53的体细胞改变 多灶性和单灶性胶质瘤患者的基因突变 患有第二次恶性肿瘤或有很强的癌症家族史。 在 此外，多灶性神经胶质瘤的肿瘤组织将在 为了检查两个不同的部位和第二个恶性肿瘤， 多灶性胶质瘤形成的单克隆与多克隆起源。 生殖系突变患者的家庭成员也将接受检测 并提供了遗传咨询 我们的研究小组发现， 差距中有两种不同类型的转录本（I型和II型） 相关结构域（GRD），其差异表达可能是 在功能上参与神经外胚层细胞的分化。 第二个目的是为了检验这一假设， I型和II型转录本的表达与 恶性、多灶性和患者继发肿瘤的发生率 恶性神经胶质瘤 最近，已经描述了一种方法， 允许鉴定不同细胞中不同表达的基因 使用聚合酶链反应来分离和克隆 单个mRNA。 本项目的第三个目标是应用 这项技术用于研究其他未知的致癌基因的存在， 或抑制基因在这个独特的亚组手术切除 多灶性胶质瘤、与第二恶性肿瘤相关的胶质瘤和 有较强家族癌症史的患者中的神经胶质瘤。 本研究将 提高我们对p53、NF 1和EGFR基因的理解 在神经外胚层恶性转化和进展中， 提供信息，以帮助确定有风险的家庭成员， 恶性肿瘤的发展。 此外，预计未知 然而，癌基因和抑制基因将被发现， 导致或促成肿瘤转化的累积事件 神经组织的结构 这项研究的结果可以打开新的 试图通过基因治疗逆转恶性表型的途径 操纵