EXPRESSION OF TUMOR SUPPRESSOR AND DNA POLYMERASE GENES IN BRAIN TUMORS

在过去的几年里，分子肿瘤学研究的许多关注点 一直致力于识别癌细胞中的非随机遗传变异， 确定遗传改变和肿瘤之间可能的相关性 表型，并找出特定的遗传改变是否可以提供 具有诊断和预后价值的信息，可能有助于 设计新的治疗方案。 在发现的遗传变化中， 在癌细胞中，肿瘤抑制基因的改变经常被 在各种人类肿瘤中检测到。 在本申请中，三条线 提出了具有潜在临床应用价值的分子遗传学研究。 首先，我们计划研究遗传变化和突变谱，如果 在脑肿瘤中的p53抑制基因中， 俄亥俄州州立大学医院和儿童医院组织网络。 在迄今为止已知的肿瘤抑制基因中，p53基因突变 抑制基因已经在多种人类癌症中检测到， 结肠、肺、食管、乳腺、肝、脑、骨的肿瘤， 网状内皮组织和造血组织。 现在我们知道， 然而，是否所有类型脑肿瘤都具有p53突变。 主义理论体系是 不知道不同类型的大脑中p53突变的谱 肿瘤是 因此，对这些突变的详细分析可能会提供线索， 这些不同肿瘤的病因学和肿瘤的功能域， p53蛋白。 其次，我们还将检查RB抑制器的状态 基因在原发性脑肿瘤组织中的表达，并与上述研究进行比较。 p53抑制基因。 就像p53一样，RB基因的染色体等位基因 通常在人类肿瘤细胞中缺失或突变。 RB和p53 抑制蛋白是一种核磷蛋白， 控制细胞生长和分化。 目前，不多 RB抑制基因缺陷（如果存在）的信息 脑肿瘤是可用的。 第三，我们将努力确定 DNA聚合酶δ基因在脑肿瘤中的表达， 肿瘤抑制蛋白和这个DNA之间可能的联系 这些肿瘤细胞中的复制酶。 一些研究表明 pol delta在DNA复制和修复中发挥作用。 最近， pol δ-辅助因子，增殖细胞核抗原（PCNA）， 其表达与细胞周期的S期密切相关， 在一些人类中显示异常表达，具有预后价值。 癌的 然而，pol δ在人类肿瘤中的表达尚未被证实。 考察 另外，肿瘤抑制基因和肿瘤细胞之间的可能联系 蛋白质和这种DNA复制酶还没有得到解决。 在 为了准备这些研究，我们收集了一些脑肿瘤 并开始分析抑癌基因缺陷的状况。 我们还克隆了全长pol δ cDNA。 根据这些分析，我们 希望能更好地了解遗传基础， 原发性脑肿瘤的肿瘤发生，并最终导致新的 这些疾病的治疗进展。

Much attention in molecular oncology research over the past few years has been on identifying non-random genetic alterations in cancer cells, defining possible correlations between genetic alterations and tumor phenotypes, and finding out if particular genetic alterations can provide information that is of diagnostic and prognostic value which may aid in designing new therapeutic regimen. Among genetic changes identified in cancer cells, alterations in the tumor suppressor genes has been frequently detected in various human tumors. In this application, three lines of molecular genetic studies with potential clinical application are proposed. First, we plan to study the genetic change and mutational spectrum, if there is any, in the p53 suppressor gene in brain tumors obtained from the Ohio State University Hospital and Children's Hospital Tissue Network. Among the tumor suppressor genes known to date, mutations in the p53 suppressor gene have been detected in various human cancers including tumors of the colon, lung, esophagus, breast, liver, brain, bone, reticuloendothelial tissues, and hemopoietic tissues. It is now known, however, whether all type of brain tumors harbor p53 mutation. Also, it is not known what spectrum of the p53 mutations in diverse types of brain tumors is. Thus, detailed analyses of these mutations may provide clues to the etiology of these diverse tumors and to the functional domains of the p53 proteins. Second, we will also examine the status of the RB suppressor gene in primary brain tumor tissues and compare with the above study on the p53 suppressor gene. Just like p53, the chromosome alleles of the RB gene are often deleted or mutated in the human tumor cells. Both RB and p53 suppressor proteins are nuclear phosphoproteins and play an important role in controlling cell growth and differentiation. Presently, not much information for the defect, if there is any, of the RB suppressor gene in brain tumors is available. Third, we will attempt to determine the expression of the DNA polymerase delta gene in brain tumors and examine the possible linkage between the tumor suppressor proteins and this DNA replication enzyme in these tumor cells. Several studies have indicated that the pol delta functions in both DNA replication and repair. Recently, a pol delta-accessory factor, Proliferating Cell Nuclear Antigen (PCNA), whose expression is strongly tied to the S phase of the cell cycle, has been shown to be aberrantly expressed with prognostic value in some human cancers. However, the expression of pol delta in human tumors has not been examined. In addition, the possible linkage between the tumor suppressor proteins and this DNA replication enzyme has not been addressed. In preparation for these studies, we have collected a few brain tumor specimens and begun to analyze the status of the suppressor gene defects. We have also cloned a full-length pol delta cDNA. Upon these analyses we hope to provide a better understanding of the genetic basis of tumorigenesis in primary brain tumors, and ultimately to lead to new advances in the treatment for these diseases.