Comprehensive genomic analysis of primary bone sarcomas reveals different genetic patterns compared with soft tissue sarcomas.

Introduction: Sarcomas are classified into two types, bone sarcoma and soft tissue sarcoma (STS), which account for approximately 1% of adult solid malignancies and 20% of pediatric solid malignancies. There exist more than 50 subtypes within the two types of sarcoma. Each subtype is highly diverse and characterized by significant variations in morphology and phenotypes. Understanding tumor molecular genetics is helpful in improving the diagnostic accuracy of tumors that have been difficult to classify based on morphology alone or that have overlapping morphological features. The different molecular characteristics of bone sarcoma and STS in China remain poorly understood. Therefore, this study aimed to analyze genomic landscapes and actionable genomic alterations (GAs) as well as tumor mutational burden (TMB), microsatellite instability (MSI), and programmed death ligand-1 (PD-L1) expression among Chinese individuals diagnosed with primary bone sarcomas and STS. Methods: This retrospective study included 145 patients with primary bone sarcomas (n = 75) and STS (n = 70), who were categorized based on the 2020 World Health Organization classification system. Results: Patients diagnosed with bone sarcomas were significantly younger than those diagnosed with STS (p < 0.01). The top 10 frequently altered genes in bone sarcoma and STS were TP53, CDKN2A, CDKN2B, MAP3K1, LRP1B, MDM2, RB1, PTEN, MYC, and CDK4.The EWSR1 fusions exhibited statistically significant differences (p < 0.01) between primary bone sarcoma and STS in terms of their altered genes. Based on the actionable genes defined by OncoKB, actionable GAs was found in 30.7% (23/75) of the patients with bone sarcomas and 35.7% (25/70) of those with STS. There were 4.0% (3/75) patients with bone sarcoma and 4.3% (3/70) patients with STS exhibited high tumor mutational burden (TMB-H) (TMB ≥ 10). There was only one patient with STS exhibited MSI-L, while the remaining cases were microsatellite stable. The positive rate of PD-L1 expression was slightly higher in STS (35.2%) than in bone sarcoma (33.3%), however, this difference did not reach statistical significance. The expression of PD-L1 in STS patients was associated with a poorer prognosis (p = 0.007). Patients with STS had a better prognosis than those with bone sarcoma, but the observed difference did not attain statistical significance (p = 0.21). Amplification of MET and MYC genes were negatively correlated with clinical prognosis in bone tumors (p<0.01). Discussion: In conclusion, bone sarcoma and STS have significantly different clinical and molecular characteristics, suggesting that it is vital to diagnose accurately for clinical treatment. Additionally, comprehensive genetic landscape can provide novel treatment perspectives for primary bone sarcoma and STS. Taking TMB, MSI, PD-L1 expression, and OncoKB definition together into consideration, there are still many patients who have the potential to respond to targeted therapy or immunotherapy.