title: Identification of p18 INK4c as a tumor suppressor gene in glioblastoma multiforme.
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 p16(INK4a) and less commonly due to genomic amplifications of individual genes encoding cyclins or cdks. Here, we describe deletion of the p18(INK4c) cdk inhibitor as a novel genetic alteration driving the pathogenesis of GBM. Deletions of p18(INK4c) often occurred in tumors also harboring homozygous deletions of p16(INK4a). Expression of p18(INK4c) was completely absent in 43% of GBM primary tumors studied by immunohistochemistry. Lentiviral reconstitution of p18(INK4c) expression at physiologic levels in p18(INK4c)-deficient but not p18(INK4c)-proficient GBM cells led to senescence-like G(1) cell cycle arrest. These studies identify p18(INK4c) as a GBM tumor suppressor gene, revealing an additional mechanism leading to aberrant activation of cyclin/cdk complexes in this terrible malignancy.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia 20057, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Solomon
authors.forename: Jung-Sik
authors.initials: JS
authors.lastname: Kim
authors.forename: Sultan
authors.initials: S
authors.lastname: Jenkins
authors.forename: Habtom
authors.initials: H
authors.lastname: Ressom
authors.forename: Michael
authors.initials: M
authors.lastname: Huang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Coppa
authors.forename: Lauren
authors.initials: L
authors.lastname: Mabanta
authors.forename: Darell
authors.initials: D
authors.lastname: Bigner
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
authors.forename: Walter
authors.initials: W
authors.lastname: Jean
authors.forename: Todd
authors.initials: T
authors.lastname: Waldman
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D014183:Transplantation, Heterologous
chemical_list: D050763:Cyclin-Dependent Kinase Inhibitor p18; D004273:DNA, Neoplasm