title: Clinical and biological significance of CDK4 amplification in well-differentiated and dedifferentiated liposarcomas.
abstract: OBJECTIVE
  The MDM2 and HMGA2 genes are consistently amplified in well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS) whereas CDK4 is frequently but not always amplified in these tumors. Our goal was to determine whether the absence of CDK4 amplification was (a) correlated to a specific clinico-histopathologic profile; and (b) compensated by another genomic anomaly involving the CCND1/CDK4/P16INK4a/RB1/E2F pathway.
  
  
  METHODS
  We compared the clinical characteristics of a series of 143 WDLPS/DDLPS with amplification of both MDM2 and CDK4 (MDM2+/CDK4+) to a series of 45 WDLPS/DDLPS with MDM2 amplification and no CDK4 amplification (MDM2+/CDK4-). We used fluorescence in situ hybridization, real time quantitative reverse transcription PCR, and immunohistochemistry to explore the status of CCND1, P16INK4a, P14ARF, and RB1.
  
  
  RESULTS
  We found that MDM2+/CDK4- WDLPS/DDLPS represent a distinct clinical subgroup with favorable prognostic features, including low-grade lipoma-like histology, peripheral location, and lower rate of recurrence. By using fluorescence in situ hybridization, we found that genomic aberrations expected to be alternative mechanisms for compensating the lack of CDK4 amplification, such as RB1 and CDKN2A deletions or CCND1 amplification, were very uncommon. In contrast, by using real time quantitative reverse transcription PCR and immunohistochemistry, we observed that overexpression of P16INK4a (and P14ARF) and CCND1 and reduced expression of RB1 were very frequent, independently of the CDK4 status.
  
  
  CONCLUSIONS
  Our results underscore the complex coordinated regulation of the RB and p53 growth-control pathways in WDLPS/DDLPS. Because the absence of CDK4 amplification is not specifically counterbalanced by a genomic alteration of the CCND1/CDK4/P16INK4a/RB1/E2F pathway, CDK4 amplification may only represent a "MDM2-HMGA2-helper" in WDLPS/DDLPS tumorigenesis.
authors.affiliation: Laboratory of Solid Tumors Genetics and Department of Pathology, Nice University Hospital, Nice, France. italiano@bergonie.org
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
authors.forename: Laurence
authors.initials: L
authors.lastname: Bianchini
authors.forename: Elisabet
authors.initials: E
authors.lastname: Gjernes
authors.forename: Frédérique
authors.initials: F
authors.lastname: Keslair
authors.forename: Dominique
authors.initials: D
authors.lastname: Ranchere-Vince
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Dumollard
authors.forename: Juliette
authors.initials: J
authors.lastname: Haudebourg
authors.forename: Agnès
authors.initials: A
authors.lastname: Leroux
authors.forename: Claire
authors.initials: C
authors.lastname: Mainguené
authors.forename: Philippe
authors.initials: P
authors.lastname: Terrier
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chibon
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.forename: Florence
authors.initials: F
authors.lastname: Pedeutour
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D054337:Cell Dedifferentiation; D002454:Cell Differentiation; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D006801:Humans; D008080:Liposarcoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4