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Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity

Nature Medicine volume 16, pages 781–787 (2010)Cite this article

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Abstract

Sarcomas are heterogeneous and aggressive mesenchymal tumors. Histological grading has so far been the best predictor for metastasis-free survival, but it has several limitations, such as moderate reproducibility and poor prognostic value for some histological types. To improve patient grading, we performed genomic and expression profiling in a training set of 183 sarcomas and established a prognostic gene expression signature, complexity index in sarcomas (CINSARC), composed of 67 genes related to mitosis and chromosome management. In a multivariate analysis, CINSARC predicts metastasis outcome in the training set and in an independent 127 sarcomas validation set. It is superior to the Fédération Francaise des Centres de Lutte Contre le Cancer grading system in determining metastatic outcome for sarcoma patients. Furthermore, it also predicts outcome for gastrointestinal stromal tumors (GISTs), breast carcinomas and lymphomas. Application of the signature will permit more selective use of adjuvant therapies for people with sarcomas, leading to decreased iatrogenic morbidity and improved outcomes for such individuals.

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Figure 1: The three main types of genomic profile established by BAC array-CGH.
Figure 2: Schematic representation of CINSARC gene set establishment procedure.
Figure 3: Metastasis-free survival analysis according to CINSARC signature and to FNCLCC grading system.
Figure 4: Metastasis-free survival analysis in clinically relevant groups.

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Acknowledgements

This work was supported by grants from the French Institut National du Cancer, the French Projets Hospitaliers de Recherche Clinique program, the European Connective Tissue Cancer Network, the Curie Institute, the Bergonie Cancer Institute and l'INSERM. The construction of the human BAC array was supported by grants from the Carte d'Identité des Tumeurs program of the French Ligue Nationale Contre le Cancer. We are grateful to members of the French Sarcoma Group for providing tumor samples : Y.-M. Robin, X. Leroy, X. Saster-Garau, B. Marquès, M-C. Château, J-P. Ghnassia and F. Mishelany, J-B. Courrège, V. Dapremont and C. Ferreira. We would like to thank R. Maki and R. Iggo for critical reading of the manuscript. We thank R. Cook for English editing.

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Authors and Affiliations

  1. Département de Pathologie, Institut Bergonié, Bordeaux, France

    Frédéric Chibon, Pauline Lagarde, Sébastien Salas, Binh Bui & Jean-Michel Coindre

  2. Institut National de la Santé et de la Recherche Médicale (INSERM) U916, Institut Bergonié, Bordeaux, France

    Frédéric Chibon, Pauline Lagarde, Binh Bui & Jean-Michel Coindre

  3. INSERM U830, Institut Curie, Paris, France

    Gaëlle Pérot, Franck Tirode, Carlo Lucchesi & Alain Aurias

  4. Département de Biostatistique, Institut Bergonié, Bordeaux, France

    Véronique Brouste

  5. Carte d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France

    Aurélien de Reynies

  6. Bioinformatique, INSERM U916, Institut Bergonié, Bordeaux, France

    Audrey Kauffmann

  7. Institut Gustave Roussy, Villejuif, France

    Philippe Terrier, Sylvie Bonvalot & Axel Le Cesne

  8. Centre Léon Bérard, Lyon, France

    Dominique Vince-Ranchère & Jean-Yves Blay

  9. Centre G. F. Leclerc, Dijon, France

    Françoise Collin

  10. Institut Universitaire de Pathologie, Lausanne, Switzerland

    Louis Guillou

  11. Centre Alexis Vautrin, Vandoeuvre-les-Nancy, France

    Agnès Leroux

  12. Université Victor Segalen Bordeaux 2, Bordeaux, France

    Jean-Michel Coindre

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  1. Frédéric Chibon
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Contributions

F. Collin, L.G., P.T., D.V.-R., A.L.C., B.B., S.B., A.L., J.-Y.B. and J.-M.C. supplied tumor tissues, did the central pathology review and collected the clinical follow-up data. F. Chibon supervised the laboratory experiments. P.L., G.P. and F. Chibon performed laboratory experiments. F.T. and C.L. developed the statistical software. A.d.R. and A.K. applied the centroid method. V.B. performed survival analysis. F. Chibon, S.S., A.d.R. and A.A. analyzed the data. F. Chibon, J.-M.C. and A.A. designed the study. F. Chibon, J.-M.C. and A.A. wrote the report. All investigators reviewed the final report.

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Correspondence to Frédéric Chibon.

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Chibon, F., Lagarde, P., Salas, S. et al. Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity. Nat Med 16, 781–787 (2010). https://doi.org/10.1038/nm.2174

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