Prognostic Implications of MDM2 and CDK4 Co-amplification in Liposarcoma: Insights from FISH analysis for Translational Oncology
Josmi James, Aidy Irman Yajid, Sahran Yahaya, Sarimah Abdullah, Sharifah Emilia Tuan Sharif
Abstract
PURPOSE: MDM2 and CDK4 amplifications are well-established diagnostic markers in liposarcoma, but the clinical relevance of their co-amplification remains underexplored. This study evaluates their amplification characteristics and combined prognostic impact to inform risk stratification and patient management. METHODS: Fluorescence in situ hybridisation (FISH) was performed on formalin-fixed paraffin-embedded samples of liposarcoma or benign lipomatous tumours (≥ 10 cm) histologically diagnosed at Hospital Pakar Universiti Sains Malaysia. Recurrence-free (RFS) and metastasis-free survival (MFS) across amplifications were determined using Kaplan-Meier. Recurrence associations with clinicopathological variables were examined using Cox regression. RESULTS: Among 86 cases, 27% were liposarcoma and 73% were benign tumours by FISH. Co-amplification (13%) was observed in all dedifferentiated liposarcoma (DDLS) and half of atypical lipomatous tumour/well-differentiated liposarcoma (ALT/WDLS) cases. MDM2 amplification without CDK4 (6%) was seen in ALT. Myxoid liposarcoma, pleomorphic liposarcoma, and benign tumours showed no amplification (81%). DDLS had higher MDM2 and CDK4 amplification ratios (4.4 and 2.8, respectively) than ALT/WDLS (2.9 and 2.6, respectively), with MDM2 consistently exceeding CDK4. Co-amplification associated with the shortest median RFS (34 months; p = 0.002) and MFS (83 months; p = 0.003). Surgery with chemotherapy (p = 0.042; HR = 26.50) associated with recurrence, while MDM2/CDK4 amplification was not an independent prognostic factor. CONCLUSION: MDM2 amplification was more consistent and quantitatively higher than CDK4, supporting its central role in tumourigenesis. While MDM2/CDK4 co-amplification was associated with poorer outcomes, it lacked independent prognostic value, reflecting the potential influence of other clinical variables. Nevertheless, co-amplification may hold clinical relevance in identifying high-risk liposarcoma subgroups.