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. © 2011 Wiley‐Liss, Inc.