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BACKGROUND: Prognostication in pediatric and young adult osteosarcoma is typically limited to metastatic status at diagnosis and tumor necrosis after chemotherapy. Despite a complex genomic landscape, few molecular biomarkers are used clinically. This study evaluates the prognostic relevance of MYC amplification and MYC protein expression.METHODS: This study analyzed 105 patients with high-grade osteosarcoma. MYC copy number was assessed via targeted sequencing, and MYC protein expression was assessed via immunohistochemistry H score. Amplification (AMP) was defined as >7 copies; high expression (EXP) was defined as an H score of >150. Correlation between AMP and EXP was calculated, and overall survival (OS) was analyzed with Kaplan-Meier and Cox models.RESULTS: Among the 105 patients (42% female; median age, 14 years; interquartile range, 11-17 years), 16% had AMP, 22% had high EXP, and 8% had both AMP and high EXP. MYC copy number positively correlated with protein expression (r = 0.53; p < .0001). With accounting for metastatic status, AMP and high EXP had lower OS (AMP vs. non-AMP: 3-year OS, 27% vs. 74%; adjusted hazard ratio [HR], 3.4; high EXP vs. low EXP: 35% vs. 77%; adjusted HR, 4.9; both p < .0001). Patients with both AMP and high EXP had markedly lower survival compared to those with non-AMP and low EXP (3-year OS, 0% vs. 79%; adjusted HR, 17.7; p < .0001).CONCLUSIONS: MYC amplification and high protein expression both independently and concurrently predict poor survival in pediatric and young adult osteosarcoma, beyond metastatic status. Incorporating MYC status into risk stratification may enhance prognostic accuracy and inform targeted therapeutic development.