title: Alterations of the p15, p16,and p18 genes in osteosarcoma.
abstract: Activation of cyclin-dependent kinases (CDKs) by interaction with cyclins regulates progression through cell cycle checkpoints. This process is counterbalanced by CDK inhibitors (CDKIs), which can inhibit progression through the cell cycle. Because CDKI expression acts to inhibit cellular proliferation, CDKIs may have a role as tumor suppressors. One class of CDKIs, characterized by the presence of ankyrin repeats, has at least four members (p15INK4B), p16INK4, p18, and p19). Two of these, p15INK4B, p16INK4, have been mapped to chromosome 9p21, a region of frequent loss in a wide variety of cancers. Alterations of p16INK4 have been detected in various tumors and cell lines. We analyzed p15INK4B, p16INK4, and p18 alterations in 52 osteosarcomas (including 11 explants), and 23 other various sarcomas. Single-stranded conformation polymorphism analysis [polymerase chain reaction (PCR-SSCP)] of the coding regions of these CDKI genes detected a missense mutation of p16INK4 exon 1 in one soft tissue sarcoma. Southern blotting detected complete deletion of p15INK4B and p16INK4 genes in osteosarcomas from 2 patients and a soft tissue sarcoma from another individual. Loss of heterozygosity (LOH) at chromosome 9p21 was observed with a microsatellite probe closely linked to the INK4 genes in the latter case. Deletions of both p15INK4B and p16INK4 genes were detected in five of eight osteosarcoma cell lines. By contrast, no alterations of p18 were detected in any sample. Together these data suggest that alterations of the p15INK4B and p16INK4 genes, but not p18, may occur in approximately 5% of sarcomas. However, deletions of the p15INK4B and P16INK4 genes are frequent in osteosarcoma cell lines and probably have a role in tumor cell growth in culture. Notably, all seven detectable deletions involved both p15INK4B and p16INK4 genes, suggesting that both contribute individual tumor suppressor activity.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, UCLA School of Medicine, Cedars-Sanai Research Institute, Los Angeles, CA 90048, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Miller
authors.forename: A
authors.initials: A
authors.lastname: Aslo
authors.forename: M J
authors.initials: MJ
authors.lastname: Campbell
authors.forename: N
authors.initials: N
authors.lastname: Kawamata
authors.forename: B C
authors.initials: BC
authors.lastname: Lampkin
authors.forename: H P
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D001483:Base Sequence; D015139:Blotting, Southern; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D017931:DNA Primers; D004791:Enzyme Inhibitors; D017353:Gene Deletion; D015321:Gene Rearrangement; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D012516:Osteosarcoma / Q000235:genetics*; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: C493966:CDKN2B protein, human; C493971:CDKN2C protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D017931:DNA Primers; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins