Project: Research project

Project Details


DESCRIPTION: Gliomas are the most common primary human brain tumors. Even
despite aggressive therapeutic treatments the most malignant of these,
glioblastoma, is still a lethal disease. If new and efficient therapeutic
approaches are to be developed then a more comprehensive understanding of
the genetics and biology of the brain tumors will be required. Despite
considerable analysis of genetic changes associated with the development of
gliomas, no glioma-specific tumor suppressor gene has been identified to
date. However, as a result of extensive cytogenetic and loss of
heterozygosity (LOH) analysis it is now clear that partial or complete loss
of chromosomes 10q and 19q occurs in the vast majority of malignant gliomas.
These observations indicate that these regions contain genes, which, as a
result of inactivation play an important role in tumorigenesis. An
important mechanism resulting in gene inactivation is through chromosome
translocations, which disrupt the genes at the breakpoints. Thus, these
translocation breakpoints pinpoint the position of the critical tumor
suppressor gene within the region of LOH. Recently, the principal
investigator has identified three glioblastoma cells, which carry
translocations involving chromosome regions 10q24 and 19q13. One of these
cell lines carries a reciprocal 1(10;19)(q24;q13) translocation and all of
these breakpoints lie exactly in the critical regions on chromosomes 10 and
19 indicated by LOH to be important. Using FISH analysis this lab has
positioned YAC clones across the breakpoints on both chromosomes of the
10;19 reciprocal translocation. The exact molecular position of the
translocation breakpoints were then identified using somatic cell hybrids
created from these cells which contain the rearranged chromosomes. They
have now isolated a smaller BAC clone from chromosome 10, which crosses the
breakpoint. The principal investigator will now use the same strategy to
isolate a BAC clone, which crosses the chromosome 19 breakpoint. Since
these BAC clones are relatively small (170Kb on average) the applicant will
use them to isolate the genes interrupted by the translocation using several
different but complementary approaches including cDNA library screening,
cDNA capture and exon trapping. The applicant will then use these genes to
analyze the large number of brain tumor samples available to determine their
wider involvement in brain tumorigenesis. The identification of the genes
which are involved in the development of malignant gliomas will not only
improve our understanding of the basic underlying mechanisms of the disease
process but also may lead to the development of a targeted therapy against
the genes and their products and also improve diagnosis and prognosis for
this highly heterogeneous group of tumors.
Effective start/end date7/8/986/30/03


  • Medicine(all)