EXPRESSION OF TUMOR SUPPRESSOR AND DNA POLYMERASE GENES IN BRAIN TUMORS

近年来，分子肿瘤学研究受到了广泛的关注

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.