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Prognostic and Pathologic Significance of Quantitative Protein Expression Profiling in Human Gliomas¹

Departments of Radiation Oncology [A. C., M. A. D., J. S. L.], Biostatistics [A. M.], and Molecular Oncology [N. J. D.], Massachusetts General Hospital, Harvard Medical School and Department of Neurosurgery [E. N., P. M. B.], Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02114

Purpose: Analysis of tumor-derived genetic lesions has provided insights into molecular pathogenesis of human gliomas. Because these changes represent only one of several mechanisms that alter gene expression during tumorigenesis, it is likely that further information will be obtained from a careful analysis of important regulatory proteins present in these tumors.

Experimental Design: We have quantified the levels of key cell cycle/signaling proteins in 94 prospectively collected, meticulously preserved, "snap frozen" glioma specimens and have compared these levels with histopathological data and patient outcome.

Results: The results of these experiments confirm that the levels of wild-type tumor suppressor proteins, such as p53, pRB, PTEN, p14^ARF, and p16^INK4, are lost or severely reduced in most gliomas, and that epidermal growth factor receptor, 2human telomerase reverse transcriptase, and cyclin-dependent kinase 4 are overexpressed frequently and with a few exceptions, almost exclusively, in glioblastomas. In addition, we report frequent underexpression of E2F-1 (in 55% of gliomas) and cyclin E overexpression (in 26% of gliomas), which have not yet been reported on the genomic level. Several of these markers significantly correlated with histopathological grade, and the levels of five proteins showed significant association with patient outcome. In particular, overexpression of epidermal growth factor receptor, human telomerase reverse transcriptase, cyclin-dependent kinase 4, and cyclin E was largely restricted to glioblastomas and was significantly associated with reduced patient survivals.

Conclusions: We conclude that the quantitation of cell cycle/signaling proteins from meticulously preserved glioma specimens provides further insights into the molecular pathogenesis of human gliomas and yields valuable prognostic information.

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