AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA
1749
Introduction: Malignant gliomas are the most common and most lethal primary brain tumor in adults. However, significant gaps exist in the current understanding of the molecular pathways involved in their genesis and clinical behavior. Therapeutic irradiation and chronic immunosuppression remain the only established risk factors, but viral infections and host genetic susceptibility have also been implicated. An association between human cytomegalovirus (HCMV) and malignant gliomas was recently reported suggesting that HCMV may play an active role in gliomagenesis. To examine this further, we used standard cytogenetic assays to measure the effects of HCMV infection on genetic instability. Methods: 35 glioma cases and 25 controls from an ongoing brain tumor study in Harris County, Texas, completed an epidemiologic questionnaire and gave a blood sample for cytogenetic analysis. Peripheral blood lymphocytes (PBLs) were isolated from each specimen, and 4 separate cultures were established for each participant. One culture was analyzed for baseline levels, one was infected with HCMV, one was treated with gamma radiation, and the last was infected with HCMV and then irradiated. The micronucleus (MN) assay was used to determine levels of chromosome breaks and rearrangements, and chromosomal aberrations were also measured as total chromatid breaks. Cells in apoptosis and stages of the cell cycle were measured by TUNEL assay. A repeated-measure analysis of variance with one between subjects factor (case-control) and one within subjects factor (treatment) was used to determine differences in mean values of the cytogenetic outcomes based on treatment type and case-control status. Results: The prevalence of chromosome breaks was higher for cultures treated with both the virus and radiation. Cultures treated with the virus alone or in conjunction with radiation showed significant increases in chromosomal rearrangements. The number of chromatid breaks was significant for each level of treatment with those being co-treated having more damage than those treated with radiation alone. Apoptosis was increased for treatment with both HCMV and radiation, and cases exhibited higher levels than controls. There was also a non-significant increase in the percentage of cells in S phase and decrease in the percentage in G1. Conclusions: Cytogenetic assays estimate the amount of damage normal cells undergo by certain stressors. We show that the amount of apoptosis and chromosomal damage in PBLs is greatly enhanced by infection with HCMV, especially with the additional stress of gamma radiation. This strengthens the argument that HCMV could modulate gliomagenesis through induction of chromosomal damage. This could be especially true for patients in which p53-modulated apoptotic pathways have been altered.