title: MTS1/p16/CDKN2 lesions in primary glioblastoma multiforme.
abstract: The multiple tumor suppressor 1 (MTS1) gene encoding the p16 inhibitor of cyclin-dependent kinase 4 is deleted or mutated in a wide variety of human tumor cell lines, but the importance of this gene as a tumor suppressor in vivo appears to be highly dependent on tumor type. Because MTS1/p16/CDKN2 and the homologous MTS2/p15 gene map to a region of chromosome 9p21, which is frequently deleted in malignant gliomas, we searched for lesions of these genes in primary biopsies of glioblastoma multiforme (GBM). Our analysis confirms a sizable frequency of homozygous deletion of MTS1/p16/CDKN2 (9/27 cases) and also reveals a low but detectable frequency of intragenic DNA lesions (one point mutation in exon 2 leading to premature termination) among GBMs that retain one or both copies of the gene. No mutations were found in exon 2 of MTS2/p15 (12 cases examined), and one GBM showed a DNA deletion breakpoint in the 30 kb between MTS1/p16/CDKN2 and MTS2/p15 resulting in deletion of MTS1/p16/CDKN2 with retention of MTS2/p15. In contrast to the high-grade tumors, none of 12 low-grade gliomas showed MTS1/p16/CDKN2 deletions. These data support a role for MTS1/p16/CDKN2 as a tumor suppressor gene in the in vivo evolution of GBMs. Given that two tumors with hemizygous MTS1/p16/CDKN2 deletions and loss of heterozygosity for chromosome 9p21 did not contain detectable intragenic mutations, there may be one or more additional relevant 9p21 tumor suppressor genes.
authors.affiliation: Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York.
authors.forename: T
authors.initials: T
authors.lastname: Moulton
authors.forename: G
authors.initials: G
authors.lastname: Samara
authors.forename: W Y
authors.initials: WY
authors.lastname: Chung
authors.forename: L
authors.initials: L
authors.lastname: Yuan
authors.forename: R
authors.initials: R
authors.lastname: Desai
authors.forename: M
authors.initials: M
authors.lastname: Sisti
authors.forename: J
authors.initials: J
authors.lastname: Bruce
authors.forename: B
authors.initials: B
authors.lastname: Tycko
mesh_terms: D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases; D004247:DNA / Q000235:genetics; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics*; D005910:Glioma / Q000235:genetics; D006801:Humans; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins
chemical_list: D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015335:Molecular Probes; D011518:Proto-Oncogene Proteins; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases