Prognostic Value of the G2 Expression Signature and MYC Overexpression in Childhood High-Grade Osteosarcoma

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PURPOSE In high-grade osteosarcoma, prognostic factors at diagnosis are insufficient for stratifying patients into relevant subgroups. Recently, a transcriptomic study developed the G1/G2 gene expression signature, in which the G2 signature was associated with unfavorable survival. An orthogonal study identified MYC amplification as an unfavorable prognostic factor using targeted next-generation sequencing. The purpose of this study was to validate the independent prognostic value and to investigate the combined prognostic value of the G1/G2 signature with MYC amplification and/or MYC expression for survival prediction. MATERIALS AND METHODS This study included pediatric and adolescent patients with high-grade osteosarcoma. RNA-seq was performed in 48 patients. Whole-exome sequencing was performed in 40 patients. Gene expression signature scores, MYC amplification (defined as >seven copies), and MYC expression levels were calculated. Multivariable Cox proportional hazards analysis was performed for event-free survival (EFS; primary end point) and overall survival (OS; secondary end point). RESULTS In the full cohort, the 3-year EFS rate was 37%. In multivariable Cox regression analysis with metastatic disease stage (n = 21, 44%) as covariate, the G2 signature and MYC expression were independently associated with worse outcomes in terms of EFS (hazard ratio [HR], 3.32 [95% CI, 1.34 to 8.21] and HR, 3.38 [95% CI, 1.71 to 6.66], respectively) and OS (HR, 4.07 [95% CI, 1.19 to 13.9] and HR, 2.88 [95% CI, 1.22 to 6.76], respectively). MYC amplification was not associated with EFS or OS in univariable analysis (HR, 1.88 [95% CI, 0.74 to 4.77] and HR, 0.79 [95% CI, 0.21 to 3.05], respectively). CONCLUSION The G2 gene expression signature and MYC expression were independently associated with unfavorable outcomes in a pediatric cohort of patients with high-grade osteosarcoma. The combined prognostic value warrants further prospective validation and could potentially serve as a stratification marker for future osteosarcoma treatment protocols.

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