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

Authors
  • Sannino, Giuseppina1
  • Marchetto, Aruna1
  • Ranft, Andreas2
  • Jabar, Susanne2
  • Zacherl, Constanze1
  • Alba-Rubio, Rebeca1
  • Stein, Stefanie1
  • Wehweck, Fabienne S1
  • Kiran, Merve M3
  • Hölting, Tilman L B1
  • Musa, Julian1
  • Romero-Pérez, Laura1
  • Cidre-Aranaz, Florencia1
  • Knott, Maximilian M L1
  • Li, Jing1
  • Jürgens, Heribert4
  • Sastre, Ana5
  • Alonso, Javier6
  • Da Silveira, Willian7
  • Hardiman, Gary8
  • And 7 more
  • 1 Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. , (Germany)
  • 2 Department of Pediatrics III, West German Cancer Centre, University Hospital Essen, Essen, Germany. , (Germany)
  • 3 Department of Pathology, Medical Faculty, Ankara Yildirim Beyazit University, Ankara, Turkey. , (Turkey)
  • 4 Department of Pediatric Hematology and Oncology, University Hospital Münster, Münster, Germany. , (Germany)
  • 5 Unidad hemato-oncología pediátrica, Hospital Infantil Universitario La Paz, Madrid, Spain. , (Spain)
  • 6 Pediatric Solid Tumour Laboratory, Institute of Rare Diseases Research (IIER), Instituto de Salud Carlos III, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CB06/07/1009; CIBERER-ISCIII), Spain. , (Spain)
  • 7 Center for Genomics Medicine, Medical University of South Carolina, Charleston, SC, USA.
  • 8 Center for Genomics Medicine, Medical University of South Carolina, Charleston, SC, USA; School of Biological Sciences, Institute for Global Food Security, Queen's University Belfast, Belfast, UK.
  • 9 Gerhard-Domagk Institute of Pathology, University Hospital of Münster, Münster, Germany. , (Germany)
  • 10 Institute of Pathology, Faculty of Medicine, LMU Munich, Germany; German Cancer Consortium (DKTK), partner site Munich, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. , (Germany)
  • 11 Department of Pediatrics III, West German Cancer Centre, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, Germany. Electronic address: [email protected] , (Germany)
  • 12 Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), partner site Munich, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: [email protected] , (Germany)
Type
Published Article
Journal
EBioMedicine
Publisher
Elsevier
Publication Date
Sep 01, 2019
Volume
47
Pages
156–162
Identifiers
DOI: 10.1016/j.ebiom.2019.08.002
PMID: 31427232
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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). 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. The laboratory of T. G. P. Grünewald is supported by grants from the 'Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der LMU München (WiFoMed)', by LMU Munich's Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, the 'Mehr LEBEN für krebskranke Kinder - Bettina-Bräu-Stiftung', the Walter Schulz Foundation, the Wilhelm Sander-Foundation (2016.167.1), the Friedrich-Baur foundation, the Matthias-Lackas foundation, the Barbara & Hubertus Trettner foundation, the Dr. Leopold & Carmen Ellinger foundation, the Gert & Susanna Mayer foundation, the Deutsche Forschungsgemeinschaft (DFG 391665916), and by the German Cancer Aid (DKH-111886 and DKH-70112257). J. Li was supported by a scholarship of the China Scholarship Council (CSC), J. Musa was supported by a scholarship of the Kind-Philipp foundation, and T. L. B. Hölting by a scholarship of the German Cancer Aid. M. F. Orth and M. M. L. Knott were supported by scholarships of the German National Academic Foundation. G. Sannino was supported by a scholarship from the Fritz-Thyssen Foundation (FTF-40.15.0.030MN). The work of U. Dirksen is supported by grants from the German Cancer Aid (DKH-108128, DKH-70112018, and DKH-70113419), the ERA-Net-TRANSCAN consortium (project number 01KT1310), and Euro Ewing Consortium (EEC, project number EU-FP7 602,856), both funded under the European Commission Seventh Framework Program FP7-HEALTH (http://cordis.europa.eu/), the Barbara & Hubertus Trettner foundation, and the Gert & Susanna Mayer foundation. G. Hardiman was supported by grants from the National Science Foundation (SC EPSCoR) and National Institutes of Health (U01-DA045300). The laboratory of J. Alonso was supported by Instituto de Salud Carlos III (PI12/00816; PI16CIII/00026); Asociación Pablo Ugarte (TPY-M 1149/13; TRPV 205/18), ASION (TVP 141/17), Fundación Sonrisa de Alex & Todos somos Iván (TVP 1324/15). Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.

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