The CDKN2A/CDKN2B/CDK4/CCND1 pathway is pivotal in well-differentiated and dedifferentiated liposarcoma oncogenesis: an analysis of 104 tumors

Genes Chromosomes Cancer. 2011 Nov;50(11):896-907. doi: 10.1002/gcc.20909. Epub 2011 Aug 24.


The MDM2 and CDK4 genes are the main targets of chromosome 12 amplification in well-differentiated and dedifferentiated liposarcomas. Nevertheless, around 10% of these tumors do not amplify CDK4. To find substitutive alterations of CDK4 amplification, we analyzed a large series of liposarcomas by array-CGH, real-time genomic PCR, gene expression array, and real-time RT-PCR. We demonstrate that an alteration in the CDKN2A/CDKN2B/CDK4/CCND1 pathway is present in almost all cases without CDK4 amplification, thereby confirming the pivotal role of this pathway in liposarcoma oncogenesis. Moreover, we show that cell cycle and differentiation are driven by a subtle and complex balance between members of this pathway. Finally, we demonstrate that in tumors without amplification/overexpression of CDK4, the chromosome 1q21-1q23 region is a preferential partner of chromosome 12 amplicon, suggesting that the mechanism of amplification is slightly different in this group of tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Differentiation / physiology
  • Comparative Genomic Hybridization
  • Cyclin D1 / genetics*
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase 4 / genetics*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p15 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Female
  • Gene Amplification
  • Gene Expression Profiling
  • Genetic Loci
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Liposarcoma / genetics*
  • Liposarcoma / metabolism
  • Liposarcoma / pathology
  • Male
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction


  • CCND1 protein, human
  • CDKN2B protein, human
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin D1
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4