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Sarcoma

Sarcoma Parallel Session

87: Differences in Gene Expression and Potential Therapeutic Targets in Recurrent Liposarcoma

Thursday, March 21, 2024
11:26am – 11:36am ET
Location: C105-C106
Disclosure(s):
Jessie M. Dalman, BA: No financial relationships to disclose
Christina V. Angeles, MD: SkylineDx: Research Grant (Ongoing)
Introduction: Liposarcoma constitutes 20% of all malignant mesenchymal neoplasms. Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are both characterized by chromosome 12q13-15 amplification. While both subtypes demonstrate high rates of recurrence, DDLPS patients experience greater mortality due to lack of effective therapies. While MDM2 and CDK4 inhibitors are being investigated, it is essential that we continue to identify molecular abnormalities related to clinical outcomes in LPS. We sought to further elucidate differences in gene regulation in WDLPS vs DDLPS and recurrent vs non-recurrent disease.


Methods: We collected WDLPS (6), WD/DDLPS (4), and DDLPS (8) samples from extremity and retroperitoneal tumors. WD/DDLPS and DDLPS cohorts were then combined to represent dedifferentiated disease (12). Differential gene expression analysis was done for bulk RNAseq data using DESeq2 R package. Samples were normalized and evaluated with principal component analysis, sample-by-sample correlation and hierarchical clustering. DDLPS was compared to WDLPS to identify differences in gene expression. Recurrent patients were compared to non-recurrent patients in the DDLPS subset. Gene set enrichment analysis (GSEA) was used for MSigDB hallmark pathways and published T-cell signatures to define upregulated and downregulated gene sets for both comparisons.


Results: Median follow-up was 2.8 years. WDLPS and DDLPS patients had similar age, sex and race. Recurrence was noted in 17% of WDLPS vs 67% of DDLPS patients. Per GSEA analysis, adipogenesis and oxidative phosphorylation pathways were significantly downregulated in DDLPS compared to WDLPS (p=3.8*10-16 and 4.3*10-9 respectively). Central memory and naïve T-cell gene signatures were significantly under-expressed in DDLPS compared to WDLPS (p=1.4*10-6 and 1.4*10-6 respectively). Within DDLPS, the adipogenesis pathway was significantly downregulated in recurrent vs non-recurrent disease (p=3.5*10-2), while no differences were seen in T-cell signature analysis. We identified 5 genes upregulated in recurrence, including genes implicated in myogenic differentiation (CMYA5, VGLL2), antagonism of tumor suppression (HPCAL4), angiogenesis and cell migration (THBS2), and advanced-stage cancers (SNCB).


Conclusions: These results identify potential genetic signatures to predict recurrence. There may be a role for further investigation of identified genes upregulated in recurrent disease as targets for therapeutic investigation, including targeting the adipogenesis pathway in DDLPS.

Learning Objectives:

  • define pathways dysregulated in dedifferentiated liposarcoma.
  • list potential gene targets for therapeutic investigation in dedifferentiated liposarcoma.
  • describe genetic hallmark pathway differences between well-differentiated and dedifferentiated liposarcoma.