Abstract
Approximately one-third of the patients with well-differentiated liposarcoma (WDLPS) will develop a local recurrence. Not much is known about the molecular relationship between the primary tumor and the recurrent tumor, which is important to reveal potential drivers of recurrence. Here we investigated the biology of recurrent WDLPS by comparing paired primary and recurrent WDLPS using microRNA profiling and genome-wide DNA methylation analyses. In total, 27 paired primary and recurrent WDLPS formalin-fixed and paraffin-embedded tumor samples were collected. MicroRNA expression profiles were determined using TaqMan® Low Density Array (TLDA) cards. Genome-wide DNA methylation and differentially methylated regions (DMRs) were assessed by methylated DNA sequencing (MeD-seq). A supervised cluster analysis based on differentially expressed microRNAs between paired primary and recurrent WDLPS did not reveal a clear cluster pattern separating the primary from the recurrent tumors. The clustering was also not based on tumor localization, time to recurrence, age or status of the resection margins. Changes in DNA methylation between primary and recurrent tumors were extremely variable, and no consistent DNA methylation changes were found. As a result, a supervised clustering analysis based on DMRs between primary and recurrent tumors did not show a distinct cluster pattern based on any of the features. Subgroup analysis for tumors localized in the extremity or the retroperitoneum also did not yield a clear distinction between primary and recurrent WDLPS samples. In conclusion, microRNA expression profiles and DNA methylation profiles do not distinguish between primary and recurrent WDLPS and no putative common drivers could be identified.
Highlights
Soft tissue sarcomas form a heterogeneous group of rare, mesenchymal tumors, of which liposarcomas comprise one of the largest subgroups.[1]
well-differentiated liposarcoma (WDLPS) are mostly localized in the extremities and the retroperitoneum, and the prognosis of these patients is significantly better than those of patients with dedifferentiated liposarcoma.[2]
WDLPS are characterized by amplification–on a neochromosome–of the 12q14-15 region, which includes the genes MDM2 and CDK4.[1]. Treatment of WDLPS consists of complete surgical resection of the tumor, occasionally combined with neoadjuvant/ adjuvant radiotherapy for tumors localized in the retroperitoneum
Summary
Soft tissue sarcomas form a heterogeneous group of rare, mesenchymal tumors, of which liposarcomas comprise one of the largest subgroups.[1]. WDLPS are mostly localized in the extremities and the retroperitoneum, and the prognosis of these patients is significantly better than those of patients with dedifferentiated liposarcoma.[2] WDLPS have a risk of dedifferentiation, potentially leading to metastatic disease with concurrent dismal prognosis. The rate of dedifferentiation in WDLPS in the extremities is extremely low, while in the retroperitoneum the risk of dedifferentiation is higher.[1] Molecularly, WDLPS are characterized by amplification–on a neochromosome–of the 12q14-15 region, which includes the genes MDM2 and CDK4.[1] Treatment of WDLPS consists of complete surgical resection of the tumor, occasionally combined with neoadjuvant/ adjuvant radiotherapy for tumors localized in the retroperitoneum. Approximately one-third of the patients will develop a local recurrence. Whereas the biology and behavior of primary WDLPS has been widely studied, there is a lack of insight in changes in microRNA expression and DNA methylation profiles between primary and recurrent WDLPS
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