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Loss of P16^INK4 Expression Is Frequent in High Grade Gliomas¹

Ludwig Institute for Cancer Research [R.N., F.B.F., H.L., W.A., W.K.C., H-J.S.H.], Department of Medicine [W. K. C., H-J. S. H.], and Center for Molecular Genetics [W. K. C.], University of California-San Diego, La Jolla, California 92093; Cancer Biology Program, Stanford University, Stanford, California 94305 [W. A.]; and Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington [M. S. B.]

P16^INK4 is a cell cycle regulator that specifically binds to and inactivates cyclin-dependent kinase 4 (CDK4). Its encoding gene (p16/CDKN2) maps to chromosome 9p21, a region that undergoes frequent loss of heterozygosity in a variety of human tumors. We have analyzed the p16/CDKN2 gene and its expression in a series of primary glioma samples. Although homozygous deletion or mutation of the p16/CDKN2 gene was uncommon in this series and P16^INK4 protein was detectable in all grade II tumors, it was present in only 50% of grade III and grade IV samples. Conversely, in some grade IV tumors the level of P16^INK4 protein was elevated; in these cases, its target, CDK4, was amplified and overexpressed. These results suggest: (a) the involvement of P16^INK4 in glioma progression; (b) that mechanisms other than mutation or deletion can down-regulate expression of the p16/CDKN2 gene; and (c) that the balance between CDK4 and its cognate inhibitor, P16^INK4, may confer a cell growth advantage and facilitate tumor progression.

¹ This work is supported in part by the CNPq/Brazilian National Research Council (W. A.).

² Fellow of the Robert Steel Foundation for Pediatric Cancer Research.

³ To whom requests for reprints should be addressed, at Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, CA 92093-0660.

Received 12/30/94. Accepted 3/ 1/95.

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