Clinical and Biological Significance of CDK4 Amplification in Well-Differentiated and Dedifferentiated Liposarcomas

Abstract

Purpose: 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. Experimental Design: 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. (Clin Cancer Res 2009;15(18):5696-703)

STAT6 is amplified in a subset of dedifferentiated liposarcoma

“…6,12 Abundant experimental evidence also supports the functional relevance of CDK4 in dedifferentiated liposarcoma. 13,14 Less common genomic events have been variably associated with particular biological features, for example, amplification of JUN and dedifferentiation. 8 The presence of STAT6 amplification demonstrated in this report, combined with the functional evidence of STAT6 dependency in dedifferentiated liposarcoma, 14 highlights the biological and potentially therapeutic relevance of STAT6 in at least a subset of dedifferentiated liposarcoma and provides a basis to explore STAT6-targeting agents 17 as a rational therapeutic strategy in dedifferentiated liposarcoma.…”

“…6,10 CDK4 gene amplification and overexpression very likely have an important role in the tumorigenic process in dedifferentiated liposarcoma, but the contribution of other genes in this amplicon has not been explored. 13,14 In addition to providing greater understanding of the pathogenesis of dedifferentiated liposarcoma, the concurrent amplification and overexpression of MDM2 and CDK4 serve as important diagnostic markers that can be detected by immunohistochemistry or FISH. 15 MDM2 and CDK4 also represent attractive potential therapeutic targets-both MDM2 inhibition and CDK4 inhibition have shown promising activity in preclinical models and are being evaluated in clinical trials.…”

Prognostic relevance of Fédération Nationale des Centres de Lutte Contre le Cancer grade and MDM2 amplification levels in dedifferentiated liposarcoma: a study of 50 cases

“…Recently, specific chromosomal copy number abnormalities associated with dedifferentiation were identified in dedifferentiated liposarcoma, but not in well-differentiated liposarcoma. Namely, 11q23-24 region, which carries several genes that are downregulated during dedifferentiation, was lost in 16 demonstrated that well-differentiated liposarcoma/dedifferentiated liposarcoma with MDM2 amplification but no CDK4 amplification has a favorable prognosis with lower rate of recurrence. Recently, Lee et al 9 investigated the prognostic significance of MDM2 and CDK4 amplification levels in a series of 56 well-differentiated liposarcoma/dedifferentiated liposarcoma using both FISH and quantitative PCR and identified high amplification levels of CDK4 as an independent adverse prognostic factor affecting overall survival and disease progression.…”

Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas

“…7 MDM2 amplification leads to the inactivation of TP53, which is rarely mutated in those tumors. 8 The pathogenesis of atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma might also be linked to several molecular events in addition to the inactivation of TP53 such as the frequent amplification of HMGA2, 5,6 CDK4, 6,9 and FRS2, 10 as well as other genes located nearby MDM2. These genes are probably not only passive passengers of the amplicons but may also have a crucial role in the genesis and progression of these tumors.…”

“…12 CDK4 is frequently but not systematically coamplified with MDM2 in atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma. 9 Among the mechanisms that have been reported to be involved in atypical lipomatous tumor/ well-differentiated liposarcoma dedifferentiation, the amplification of JUN (1p32) or MAP3K5 (6q23.3) (that encodes a kinase acting upstream of JUN) has been suggested because of a correlation between JUN amplification and dedifferentiated liposarcoma histotype. 13,14 Remarkably, JUN can regulate the activity of transcription factors involved in adipogenesis.…”