The CDKN2A/CDKN2B/CDK4/CCND1 pathway is pivotal in well‐differentiated and dedifferentiated liposarcoma oncogenesis. An analysis of 104 tumors

Abstract

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.

A newly characterized human well-differentiated liposarcoma cell line contains amplifications of the 12q12-21 and 10p11-14 regions

“…We have emitted the hypothesis these co-amplified regions might provide neocentromeric sequences to the giant markers that lack alpha-satellite sequences [15,23]. The 1q23-24 amplicon [30,56] has been recently suggested to be associated more frequently with WDLPS/DDLPS lacking CDK4 amplification [7,64]. The 10p11-14 region is rarely co-amplified with 12q in WDLPS/DDLPS, only a handful of cases have been described [22,65].…”

AMACRAmplification in Myxofibrosarcomas: A Mechanism of Overexpression That Promotes Cell Proliferation with Therapeutic Relevance

“…As a prototypic D-type cyclin, cyclin D1 binds to cyclin-dependent kinases (CDK) 4/6 to phosphorylate retinoblastoma (Rb), thereby unleashing E2F family members to transactivate genes required for progression from the G 1 to S-phase (30). By amplification or translocation, the constitutive overexpression of D-type cyclins or associated CDK4/6 is an established oncogenic aberration in various cancer types (7,(30)(31)(32)(33), including myxofibrosarcomas with CDK6 amplification. In this study, AMACR overexpression in myxofibrosarcoma cells could increase cyclin D1 expression at the mRNA and protein levels, whereas the mechanisms underlying this regulatory link remain to be elucidated.…”

Differential expression of cyclin G2, cyclin-dependent kinase inhibitor 2C and peripheral myelin protein 22 genes during adipogenesis

“…For example, CDK4 is the main target for amplification of chromosome 12 in well-differentiated or dedifferentiated liposarcomas (Louis-Brennetot et al, 2011), whereas CDKN2C is one of the main inhibitors of CDK4, and, thus, may provide a prospective remedy for this disease. However, more in-depth studies still need to be done before application of these cell cycle inhibitors in these areas.…”