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Identification of Differentially Expressed Genes in Human Gliomas by DNA Microarray and Tissue Chip Techniques

Department of Pathology [S-L. S., P. K. S., H. K. H., H. J. H.], Laboratory of Molecular Pathology [S-L. S., P. K. S.], and Department of Neurosurgery [P. T. H.], Tampere University Hospital, FIN-33521, Tampere, Finland; Institute of Pathology, University of Basel, Basel 4003, Switzerland [P. S.]; and Laboratory of Cancer Genetics, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892-4470 [O-P. K., J. K.]

New genomic large-scale screening techniques have made the task of establishing an accurate molecular fingerprint of cancer cells feasible. Here, we have used a two-phase strategy for identification of molecular alterations in gliomas. First, cDNA microarrays (Clontech Laboratories, Inc., Research Genetics) were used to pinpoint differentially expressed genes between normal brain and diffuse astrocytomas (grades II–IV), and between a primary tumor and a later tumor reoccurrence in the same patient. More than 200 gene expression alterations were detected from glioblastomas, whereas relatively few changes were seen in grade II and grade III tumors. The most distinct progression-related expression change was the up-regulation of the insulin-like growth factor binding protein 2 (IGFBP2) gene. Second, a high-density tissue microarray of 418 brain tumors was constructed and used for clinical validation of gene expression changes. Strong expression of IGFBP2 was associated with progression and poor patient survival in diffuse astrocytomas (P < 0.0001). Third, comparisons of the data between (a) multiple spots retrieved from one predefined tumor region (IGFBP2 and vimentin immunohistochemistry, 20 tumors) or between (b) standard slides and arrayed tissues (p53 immunohistochemistry, 42 tumors) revealed very little variation. In conclusion, the combined use of DNA microarrays and tissue microarrays offers a powerful strategy for rapid identification and thorough characterization of differentially expressed genes in gliomas.

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