Our central hypothesis is that a brain tumor patient's therapy selects intrinsically resistant cells which share genetic changes that confer a selective survival advantage, enabling such cells to repopulate the tumor mass. This hypothesis is predicated on our previous studies in which tumors selected with BCNU in vitro demonstrated a non-random karyotypic deviation consisting of polyploidy chromosomes 7 and 22. This cytogenetic abnormality was detected in approximately 30% of the tumors with standard cytogenetic techniques. To determine if this same phenomenon occurred following a patient's adjuvant therapy, we compared a series of primary and recurrent tumor tissues from individuals who were treated with irradiation and BCNU. Cytogenetic analysis of the recurrent tumors demonstrated that the dominant population in some of these tumors had an over-representation of chromosomes 7 and 22. Most recurrent tumors had very complex karyotypes, containing two normal and or derivative chromosomes 7 and 22, or they appeared to have lost chromosomes 7 and/or 22. However, each of these recurrent tumor samples also had a number of marker chromosomes that could not be identified by chromosome banding techniques. To determine the origin of these marker chromosomes we used chromosome specific paints to chromosomes 1, 6, 7, 10, 15, 21, 22, X or Y. We found that both derivative chromosomes and markers retained segments of chromosomes 7 and 22 in every recurrent tumor, while all other chromosomes tested were randomly retained. We now hypothesize that such segments are regions of chromosome 7 and 22 containing genes that provide a selective survival and/or growth advantage to cells, resulting in the growth of recurrent tumor.
Specific Aim 1 proposes to complete the collection of primary/recurrent tumor pairs from patients who have different grades of gliomas and received other therapies. While standard and molecular cytogenetics have provided strong evidence for the importance of genes on chromosomes 7 and 22, they do not demonstrate that these genes are directly involved in drug resistance or growth.
Specific Aim 2 tests the hypothesis that genes retained on these segments are related to cellular resistance and/or growth.
Specific Aim 3 will localize specific regions of chromosomes 7 and 22 retained in these tumors. Thus, Specific Aims 1-3 will allow us to localize regions of chromosome 7/22 containing genes that have the potential to confer a selective survival and/or growth advantage to tumor cells.
Specific Aim 4 is designed to analyze patients' tissues directly so as to provide the in vivo correlate to our in vitro analyses. Our long-range goal is to identify specific genetic changes within the architecture of the brain tumor and identify genes that will provide insight to allow the development of new therapeutic strategies for the treatment of central nervous system malignancies.
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