LOSS OF P16(INK4) EXPRESSION IS FREQUENT IN HIGH-GRADE GLIOMAS

P16(INK4) is a cell cycle regulator that specifically binds to and ina ctivates cyclin-dependent kinase 4 (CDK4). Its encoding gene (p16/CDKN 2) maps to chromosome 9p21, a region that undergoes frequent loss of h eterozygosity in a variety of human tumors. We have analyzed the p16/C DKN2 gene and its expression in a series of primary glioma samples. Al though homozygous deletion or mutation of the p16/CDKN2 gene was uncom mon in this series and p16(INK4) protein was detectable in all grade I I 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 w as elevated; in these cases, its target, CDK4, was amplified and overe xpressed. These results suggest: (a) the involvement of p16(INK4) in g lioma 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.