Abstract
Soft tissue sarcoma (STS) represents an uncommon and heterogenous group of malignancies, and poses substantial therapeutic challenges. Pyroptosis has been demonstrated to be related with tumor progression and prognosis. Nevertheless, no studies exist that delineated the role of pyroptosis-related genes (PRGs) in STS. In the present study, we comprehensively and systematically analyzed the gene expression profiles of PRGs in STS. The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were utilized to identify differentially expressed PRGs. In total, 34 PRGs were aberrantly expressed between STS and normal tissues. Several PRGs were validated with RT-qPCR. Consensus clustering analysis based on PRGs was conducted to divide STS patients into two clusters, and significant survival difference was observed between two distinct clusters (p = 0.019). Differentially expressed genes (DEGs) were identified between pyroptosis-related clusters. Based on the least absolute shrinkage and selection operator (LASSO) COX regression analysis, the pyroptosis-related gene signature with five key DEGs was constructed. The high pyroptosis-related risk score group of TCGA cohort was characterized by poorer prognosis (p < 0.001), with immune infiltration and function significantly decreased. For external validation, STS patients from Gene Expression Omnibus (GEO) were grouped according to the same cut-off point. The survival difference between two risk groups of GEO cohort was also significant (p < 0.001). With the combination of clinical characteristics, pyroptosis-related risk score was identified to serve as an independent prognostic factor for STS patients. In conclusion, this study provided a comprehensive overview of PRGs in STS and the potential role in prognosis, which could be an important direction for future studies.
Highlights
Soft tissue sarcomas (STSs) comprise a rare group of heterogenous tumor cells, which account for only 1% of all adult malignancies (Gamboa et al, 2020)
We found that 34 pyroptosis-related genes (PRGs) were differentially expressed (p < 0.05), among which 14 genes (CASP3, CASP5, CASP6, DHX9, GSDMA, GZMA, GZMB, IL1B, NLRC4, NLRP3, NLRP7, NOD2, PYCARD, TNF) were upregulated and 20 genes (APIP, CASP4, CASP8, CASP9, ELANE, FOXO3, GPX4, GSDMB, GSDMC, GSDME, IL18, IL6, NLRP1, NLRP2, NLRP6, NOD1, PJVK, PLCG1, PRKACA, SCAF11) were downregulated in STS group (Figure 2A, Supplementary Figure S1A)
The expression levels of several key PRGs including CASP3, IL1B and DHX9 were significantly higher in the human synovial sarcoma cells SW-982 and hSS-005R, compared with those in the human skin fibroblast cell line (HSF)
Summary
Soft tissue sarcomas (STSs) comprise a rare group of heterogenous tumor cells, which account for only 1% of all adult malignancies (Gamboa et al, 2020). Surgical procedures are the cornerstones of STS treatment (Crago and Brennan, 2015). The past few decades have witnessed the evolution of therapeutic strategies for STS, with the collaboration of multidisciplinary team (MDT) including radiologists, pathologists, oncologists and surgical specialists (Gamboa et al, 2020). For elderly patients with STS, 5-years relative survival was below 50% (Hoven-Gondrie et al, 2016). STS was characterized by the susceptibility to distant metastasis and recurrence. Half of patients with localized STS developed distant metastasis, especially to the lung and leading to poor prognosis (Navarria et al, 2015; Gamboa et al, 2020). Novel therapeutic targets and reliable prognostic model need to be identified for effective and personalized treatment
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