EXPRESSION OF TUMOR SUPPRESSOR AND DNA POLYMERASE GENES IN BRAIN TUMORS

  • Pearl, Dennis Keith (PI)
  • YATES, ALLAN JAMES (PI)
  • Chang, Long Sheng (PI)
  • NEWTON, HERBERT (PI)
  • Schwartzbaum, Judith (PI)
  • MAMRAK, SANDRA (PI)
  • YATES, ALAN (PI)
  • PRIOR, THOMAS (PI)

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date1/1/018/31/96