Abstract
BackgroundSurgery, adjuvant chemotherapy, and radiotherapy are the primary treatment options for soft tissue sarcomas (STSs). However, identifying ways to improve the prognosis of patients with STS remains a considerable challenge. Evidence shows that the dysregulation of alternative splicing (AS) events is involved in tumor pathogenesis and progression. The present study objective was to identify survival-associated AS events that could serve as prognostic biomarkers and potentially serve as tumor-selective STS drug targets.MethodsSTS-specific ‘percent spliced in’ (PSI) values for splicing events in 206 STS samples were downloaded from The Cancer Genome Atlas SpliceSeq® database. Prognostic analyses were performed on seven types of AS events to determine their prognostic value in STS patients, for which prediction models were constructed with the risk score formula sumnolimits_{i}^{n} {PSIi; *;beta i}. Prediction models were also constructed to determine the prognostic value of AS events, and Spearman’s rank correlation coefficients were calculated to determine the degree of correlation between splicing factor expression and the PSI values.ResultsA total 10,439 events were found to significantly correlate with patient survival rates. The area under the time-dependent receiver operating characteristic curve for the prognostic predictor of STS overall survival was 0.826. Notably, the splicing events of certain STS key genes were significantly associated with STS 2-year overall survival in the present study, including exon skip (ES) events in MDM2 and EWSR1, alternate terminator events in CDKN2A and HMGA2 for dedifferentiated liposarcoma, ES in MDM2 and alternate promoter events in CDKN2A for leiomyosarcoma, and ES in EWSR1 for undifferentiated pleomorphic sarcoma. Moreover, splicing correlation networks between AS events and splicing factors revealed that almost all of the AS events showed negatively correlations with the expression of splicing factors.ConclusionAn in-depth analysis of alternative RNA splicing could provide new insights into the mechanisms of STS oncogenesis and the potential for novel approaches to this type of cancer therapy.
Highlights
Surgery, adjuvant chemotherapy, and radiotherapy are the primary treatment options for soft tissue sarcomas (STSs)
The splicing events of certain STS key genes were significantly associated with STS 2-year overall survival in the present study, including exon skip (ES) events in MDM2 and EWSR1, alternate terminator events in CDKN2A and HMGA2 for dedifferentiated liposarcoma, exon skips (ESs) in MDM2 and alternate promoter events in CDKN2A for leiomyosarcoma, and ES in EWSR1 for undifferentiated pleomorphic sarcoma
One type of alternative splicing (AS) event was detected in most genes, there were some exceptions; generally, it was demonstrated that 2–3 splicing events could be attributed to one gene, with a maximum of 5 types of AS events observable for a single gene
Summary
Adjuvant chemotherapy, and radiotherapy are the primary treatment options for soft tissue sarcomas (STSs). Identifying ways to improve the prognosis of patients with STS remains a considerable challenge. The present study objective was to identify survival-associated AS events that could serve as prog‐ nostic biomarkers and potentially serve as tumor-selective STS drug targets. Soft tissue sarcomas (STSs), which arise predominantly from the embryonic mesoderm, are a group of rare malignancies with high histological heterogeneity within each subtype [1]. More than 50 separate histologic STS subtypes have been identified, and the most common are liposarcoma (LPS), leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), malignant peripheral nerve sheath tumors, and synovial sarcoma [5]. Further studies are warranted to elucidate the molecular characteristics of these tumors, and the identification of additional diagnostic markers would be extremely beneficial in the clinical management of all STS patients
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