ARTICLE ABSTRACT
Genomic alterations leading to aberrant activation of cyclin/cyclin-dependent kinase (cdk) complexes drive the pathogenesis of many common human tumor types. In the case of glioblastoma multiforme (GBM), these alterations are most commonly due to homozygous deletion of p16INK4a and less commonly due to genomic amplifications of individual genes encoding cyclins or cdks. Here, we describe deletion of the p18INK4c cdk inhibitor as a novel genetic alteration driving the pathogenesis of GBM. Deletions of p18INK4c often occurred in tumors also harboring homozygous deletions of p16INK4a. Expression of p18INK4c was completely absent in 43% of GBM primary tumors studied by immunohistochemistry. Lentiviral reconstitution of p18INK4c expression at physiologic levels in p18INK4c-deficient but not p18INK4c-proficient GBM cells led to senescence-like G1 cell cycle arrest. These studies identify p18INK4c as a GBM tumor suppressor gene, revealing an additional mechanism leading to aberrant activation of cyclin/cdk complexes in this terrible malignancy. [Cancer Res 2008;68(8):2564–9]
