title: CDK4 and MDM2 gene alterations mainly occur in highly proliferative and aggressive mantle cell lymphomas with wild-type INK4a/ARF locus.
abstract: Amplification of 12q13 locus occurs in some mantle cell lymphomas (MCL), potentially involving CDK4 and MDM2 genes. To determine the role of these genes in MCL, we have examined their gene status and expression and their relationship to INK4a/ARF and p53 gene aberrations in 69 tumors. Increased CDK4 gene copy number was detected in 4 of 19 (21%) highly proliferative blastoid variants and was associated with mRNA and protein overexpression. Three additional cases showed mRNA overexpression with no structural alterations of the gene. MDM2 gene overexpression was detected in three blastoid tumors (16%) with no relationship to gene copy gains. INK4a/ARF and p53 aberrations were observed in 13 and 12 tumors, respectively. Four of the seven lymphomas with CDK4 aberrations had concurrent inactivation of p53 gene, whereas only one case had a concomitant homozygous deletion of INK4a/ARF. No other gene alterations were found in the three cases with MDM2 overexpression. Patients with INK4a/ARF deletions or simultaneous aberrations of p53 and CDK4 had a significantly shorter median survival (17 months) than patients with isolated alterations of p53, MDM2, or CDK4 (32 months) and patients with no alterations in any of these genes (77 months). The prognostic impact of the concomitant oncogenic alterations of the p14ARF/p53 and p16INK4a/CDK4 pathways was independent of the proliferation of the tumors. These findings indicate that CDK4 and MDM2 gene alterations mainly occur in MCL with a wild-type INK4a/ARF locus and may contribute to the higher proliferation and more aggressive behavior of the tumors.
authors.affiliation: Department of Pathology and Hematology, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Hernández
authors.forename: Silvia
authors.initials: S
authors.lastname: Beà
authors.forename: Magda
authors.initials: M
authors.lastname: Pinyol
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Tiemo
authors.initials: T
authors.lastname: Katzenberger
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Francesc
authors.initials: F
authors.lastname: Bosch
authors.forename: Armando
authors.initials: A
authors.lastname: López-Guillermo
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.forename: Emili
authors.initials: E
authors.lastname: Montserrat
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics*; D000483:Alleles; D048708:Cell Growth Processes / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis / Q000235:genetics*; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D020727:ADP-Ribosylation Factors