Alteration in DNA sequence copy number, in the form of loss, gain and amplification, is one way by which gene expression and function can be modified. Determining copy number changes facilitates the identification of tumor-related genes and pathways involved in tumor initiation and progression. Knowledge of DNA copy number aberrations can also provide useful prognostic information. The clinical relevance of 1p and 19q loss in anaplastic oligodendrogliomas as strong predictors of chemotherapeutic response and survival has been well documented. We have shown, by using conventional comparative genomic hybridization (CGH) that in anaplastic astrocytomas, that extent of chromosome 7 copy number increase correlates with patient survival. Our CGH analysis also showed that glioblastomas could be divided into distinct genetic subgroups based on the DNA copy number information. In addition, we have identified novel altered loci in these tumors, which need to be further defined to identify the respective genes.

Current research is focused on the development and application of DNA-based microarray CGH (array CGH) to map DNA copy number aberrations in different genetic subgroups of brain tumors. We have used a series of oligodendrogliomas to define loss of 1p and 19q copy number by array CGH and compared it to loss of heterozygosity (LOH) and fluorescence in situ hybridization (FISH), two procedures that have been routinely used by our laboratory for assaying 1p/19q loss. Array CGH correlated well with LOH and FISH and has the potential to be used as a diagnostic tool in the future. We have also used overlapping clones as targets and defined a high- resolution map of the 1q32 amplicon in glioblastoma. In the future, we hope to extend analysis to other clinically relevant loci in the genome. To this end, we have recently constructed a ~1.4Mb BAC array representing the human genome and several regions that may have prognostic importance in malignant gliomas. Our long term goal is to produce a high resolution map of malignant brain tumors from different grades, identify and characterize the genes driving these aberrations and assess their role as diagnostic and prognostic markers.