The characterisation of mdm2 and cdk4 gene amplification and their association with recurrence in lipomatous tumours

• Main Author: James, Jessinntha Spt
• Format: Thesis
• Language: English
• Published: 2025
• Subjects: R Medicine; RC254-282 Neoplasms. Tumors. Oncology (including Cancer)
• Online Access: http://eprints.usm.my/63183/

MDM2 and CDK4 are frequently amplified genes in liposarcoma, particularly in atypical lipomatous tumour/well-differentiated liposarcoma (ALT/WDLS) and dedifferentiated liposarcoma (DDLS). Although the individual oncogenic role of MDM2 and CDK4 genes are well established, the prevalence and ratio of their concurrent amplification, as well as their prognostic significance in liposarcoma, remain unclear. The aim of this study was to evaluate MDM2 and CDK4 amplification ratios across lipomatous tumour subtypes, determine their concurrent amplification statuses, and assess associations with patients’ prognosis. Clinicopathological data of cases histologically diagnosed as liposarcoma of any size or benign lipomatous tumours measuring at least 10 cm (≥10 cm), at Hospital Pakar Universiti Sains Malaysia (HPUSM) between January 2014 and May 2021, were retrospectively retrieved from Laboratory Information System of Pathology Department, HPUSM. Formalin-fixed paraffin-embedded tissue samples of eligible cases were subjected to fluorescence in situ hybridisation (FISH) for MDM2 and CDK4 gene amplification detection. Amplification ratio was determined by comparing MDM2 or CDK4 mean copy number with centromere 12 signals, where ratios more than 2.0 indicated amplification, and ratio less than 2.0 indicated no amplification. Recurrence-free and metastasis-free survival across amplification groups were evaluated using Kaplan-Meier survival analysis and compared with log-rank statistics. Prognostic factors of recurrence were analysed using Cox proportional hazard regression. Among 86 cases 23 (27%) were liposarcoma and 63 (73%) were benign lipomatous tumours (≥10 cm) following reclassification by FISH. MDM2 and CDK4 co-amplification (MDM2+/CDK4+; 13%) was observed in all (6/6) DDLS and half (5/10) of ALT/WDLS cases. Five MDM2-amplified cases lacked CDK4 amplification (MDM2+/CDK4-; 6%), all detected in ALT. No amplification of either gene (MDM2-/CDK4-; 81%) was detected in myxoid liposarcoma, pleomorphic liposarcoma, or benign tumours. DDLS showed higher MDM2 and CDK4 amplification ratios (4.4 and 2.8, respectively) than ALT/WDLS (2.9 and 2.6, respectively). In both subtypes, MDM2 amplification ratio exceeded CDK4. MDM2+/CDK4+ group had the shortest recurrence-free (p=0.002; median 34 months) and metastasis-free survival (p=0.003; median 83 months) compared to other groups. Multivariate analysis showed recurrence was significantly associated with surgery combined with chemotherapy (p=0.021), but MDM2 and CDK4 amplification was not an independent prognostic factor. In 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