Gene expression and immunohistochemical analyses identify SOX2 as major risk factor for overall survival and relapse in Ewing sarcoma patients

Sannino, Giuseppina; Marchetto, Aruna; Ranft, Andreas; Jabar, Susanne; Zacherl, Constanze; Alba-Rubio, Rebeca; Stein, Stefanie; Wehweck, Fabienne S.; Kiran, Merve M.; Hölting, Tilman L.B.; Musa, Julian; Romero-Pérez, Laura; Cidre-Aranaz, Florencia; Knott, Maximilian M.L.; Li, Jing; Jürgens, Heribert; Sastre, Ana; Alonso, Javier; Da Silveira, Willian; Hardiman, Gary; Gerke, Julia S.; Orth, Martin F.; Hartmann, Wolfgang; Kirchner, Thomas; Ohmura, Shunya; Dirksen, Uta; Grünewald, Thomas G.P.

Abstract

Background: Up to 30-40% of Ewing sarcoma (EwS) patients with non-metastatic disease develop local or metastatic relapse within a time span of 2-10 years. This is in part caused by the absence of prognostic biomarkers that can identify high-risk patients and thus assign them to risk-adapted monitoring and treatment regimens. Since cancer stemness has been associated with tumour relapse and poor patient outcomes, 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 - which was previously described to contribute to the undifferentiated phenotype of EwS.

Methods: Two independent patient cohorts, one consisting of 189 retrospectively collected EwS tumours with corresponding mRNA expression data (test-cohort) and the other consisting of 141 prospectively collected formalin-fixed and paraffin-embedded resected tumours (validation and cohort), were employed to analyse SOX2 expression levels through DNA microarrays or immunohistochemistry, respectively, and to compare them with clinical parameters and patient outcomes. Two methods were employed to test the validity of the results at both the mRNA and protein levels.

Findings: Both cohorts showed that only a subset of EwS patients (16-20%) expressed 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 poor survival (HR = 3·19; 95%CI 1·74-5·84; p < 0·01) that is independent from metastasis and other known clinical risk-factors at the time of diagnosis. Univariate analyses demonstrated that SOX2-high expression was correlated with tumour relapse (p = 0·002). The median first relapse was at 14·7 months (range: 3·5-180·7).

Interpretation: High SOX2 expression constitutes an independent prognostic biomarker for EwS patients with poor outcomes. This may help to identify patients with localised disease who are at high risk for tumour relapse within the first two years after diagnosis.

• Journal Article Type: Article
• Acceptance Date: Aug 1, 2019
• Online Publication Date: Aug 16, 2019
• Publication Date: 2019-09
• Deposit Date: Oct 25, 2024
• Publicly Available Date: Oct 25, 2024
• Journal: EBioMedicine
• Electronic ISSN: 2352-3964
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 47
• Pages: 156-162
• DOI: https://doi.org/10.1016/j.ebiom.2019.08.002