Degree of MDM2 Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma

Abstract

Background Dedifferentiated liposarcomas (DDLPS) are mesenchymal tumors associated with universally poor response to treatment. Genomic amplification of murine double minute 2 (MDM2) is used as a diagnostic biomarker; however, no established biomarkers exist to guide DDLPS treatment. In the largest study of its kind, we report that the extent of MDM2 amplification, not simply the presence of MDM2 amplification, may be biologically important to the actions of DDLPS. Patients and Methods The distribution of MDM2 amplification in DDLPS was assessed using data from a commercial sequencing laboratory (n = 642) and The Cancer Genome Atlas (n = 57). Data from two retrospective clinical trials (n = 15, n = 16) and one prospective clinical trial (n = 25) were used to test MDM2’s utility as a clinical biomarker. in vitro and in vivo assessments were conducted in DDLPS cell lines. Results Genomic MDM2 amplification follows a highly reproducible log‐normal distribution. In patients with DDLPS treated with complete tumor resection, elevated MDM2 was associated with shortened time to recurrence as measured by genomic amplification (p = .003) and mRNA expression (p = .04). In patients requiring systemic therapy, higher MDM2 amplification was associated with reduced overall survival (p = .04). Doxorubicin treatment of DDLPS cells in vitro demonstrated variable sensitivity based on baseline MDM2 levels, and doxorubicin treatment elevated MDM2 expression. In vivo, treatment with doxorubicin followed by an MDM2 inhibitor improved doxorubicin sensitivity. Conclusion MDM2 amplification levels in DDLPS follow a reproducible distribution and are associated with clinical outcomes and drug sensitivity. These results suggest that a prospective study of MDM2 as a predictive biomarker in DDLPS is warranted. Implications for Practice No validated biomarkers exist for treatment selection in dedifferentiated liposarcoma (DDLPS). Although murine double minute 2 (MDM2) is currently used for diagnosis, the clinical relevance of MDM2 amplification has yet to be fully assessed. This study found that MDM2 amplification follows a predictable distribution in DDLPS and correlates with clinical and biological outcomes. These data suggests that MDM2 amplification may be a useful biomarker in DDLPS.

Prognostic significance of the MDM2/HMGA2 ratio and histological tumor grade in dedifferentiated liposarcoma

“…15,16 High-amplification levels of MDM2 have been reported to correlate with poor outcomes in DDLPS. 17,18 In this study, although the MDM2 amplification level tended to be associated with poor OS, the correlation was not signifi- was reported to be associated with WDLPS histological type and F I G U R E 7 Association of distant metastasis-free survival (DMFS) with A, histological tumor grade, B, cellular atypia, C, MDM2 immunoreactivity, and D, HMGA2 immunoreactivity good prognosis in a study including both WDLPS and DDLPS cases. 7 However, another study showed that HMGA2 was significantly overexpressed in DDLPS samples compared with WDLPS samples from the same cases and that HMGA2 rearrangements occurred more frequently in DDLPS components.…”

MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models

“…Thus, an amplification in MDM2 results in a shift towards pro-growth pathways. Our previous work demonstrated that higher levels of MDM2 amplification are associated with worsened overall survival and resistance to DNA-damaging chemotherapy in liposarcomas [8,9]. Interestingly, although DDLPS are of fat origin, they produce scant fat themselves and resemble undifferentiated pleomorphic or spindle cell sarcoma, typically showing moderate or high cellularity, with moderate to marked pleomorphism [10].…”

A review of retroperitoneal liposarcoma genomics

“…In the largest study of its kind Bill et al correlated the degree of MDM2 amplification with clinical and biological outcomes. Elevated MDM2, as measured by genomic amplification and mRNA expression was associated with a shortened time to recurrence [43]. Other studies have confirmed a higher MDM2 copy number is associated with poorer outcomes, poorer response to cytotoxic therapy and interestingly a higher propensity for a retroperitoneal location [44,45].…”