SOX2 expression identifies Ewing sarcoma patients with high risk for tumor relapse and poor survival

Sannino, G.; Marchetto, A.; Ranft, A.; Jabar, S.; Zacherl, C.; Alba-Rubio, R.; Stein, S.; Wehweck, F. S.; Kiran, M. M.; Hoelting, T. L. B.; Musa, J.; Romero-Perez, L.; Cidre-Aranaz, F.; Knott, M. M. L.; Li, J.; Juergens, H.; Sastre, A.; Alonso, J.; Da Silveira, W.; Hardiman, G.; Gerke, J. S.; Orth, M. F.; Hartmann, W.; Kirchner, T.; Ohmura, S.; Dirksen, U.; Grunewald, T. G. P.

doi:10.1101/498253

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bioRxiv · 10.1101/498253

SOX2 expression identifies Ewing sarcoma patients with high risk for tumor relapse and poor survival

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Abstract

Purpose: Up to 30-40% of Ewing sarcoma (EwS) patients with non-metastatic disease develop local or metastatic relapse within a time range of 2-10 years. This is in part caused by the absence of prognostic biomarkers that can identify high-risk patients to assign them to risk-adapted monitoring and treatment regimens. Since cancer stemness has been associated with tumor relapse and poor outcome, we investigated in the current study the prognostic potential SOX2 (sex determining region Y box 2) - a major transcription factor involved in development and stemness - previously described to contribute to the undifferentiated phenotype of EwS. Methods: Two independent patient cohorts, one consisting of 189 retrospectively collected EwS tumors with corresponding mRNA expression data (test cohort) and the other of 141 prospectively collected formalin-fixed and paraffin embedded resected tumors (validation cohort), were employed to analyze SOX2 expression levels by DNA microarrays or immunohistochemistry, respectively, and to compare them with clinical parameters and patient outcome. Two methods were employed to test the validity of the results at both mRNA and protein levels. Results: Both cohorts showed that only a subset of EwS patients (16-20%) express high SOX2 mRNA or protein levels, which significantly correlated with poor overall survival. Multivariate analyses of our validation cohort revealed that high SOX2 expression represents a major risk factor for survival (HR=3.19; P<0.01) that is independent from metastasis and other known clinical risk-factors at time of diagnosis. Univariate analysis demonstrated that SOX2-high expression correlated with tumor relapse (P=0.001). Median first relapse was at 14.7 months (range: 3.5-180.7). Conclusions: High SOX2 expression constitutes an independent prognostic biomarker for EwS patients with poor outcome, which may help to identify patients with localized disease who are at high risk for tumor relapse within the first two years after diagnosis.

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Sannino, G., Marchetto, A., Ranft, A., Jabar, S., Zacherl, C., Alba-Rubio, R., Stein, S., Wehweck, F. S., Kiran, M. M., Hoelting, T. L. B., Musa, J., Romero-Perez, L., Cidre-Aranaz, F., Knott, M. M. L., Li, J., Juergens, H., Sastre, A., Alonso, J., Da Silveira, W., Hardiman, G., Gerke, J. S., Orth, M. F., Hartmann, W., Kirchner, T., Ohmura, S., Dirksen, U., Grunewald, T. G. P.. 2018-12-17. SOX2 expression identifies Ewing sarcoma patients with high risk for tumor relapse and poor survival. https://doi.org/10.1101/498253

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