Institut Bergonié
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Fréderic Chibon

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Group members and Contact details

Frederic Chibon graduated in molecular biology and genetics from the University of Paris 7 and joined Alain Aurias's lab at the Curie Institute in Paris in 1997. He obtained his PhD in molecular cytogenetics for work performed in the Aurias lab. He was appointed as a post-doc in Jean-Michel Coindre's group at the Bergonie Cancer Institute in 2004 and promoted to an independent group leader position in 2005. In 2011 he was appointed to an INSERM research position. His lab studies the molecular cytogenetics of sarcomas. chibon

Understanding sarcomas with complex genetics

The Sarcoma team has three main goals: to understand the genetic basis of sarcoma formation; to understand the function of genes defective in sarcomas; and to develop tools for diagnosis, prognosis and targeted therapy.

Sarcomas are heterogeneous and aggressive mesenchymal tumours. Traditionally, they are divided into more than 50 histological groups, with more than 40% classified as Malignant Fibrous Histiocytomas (MFH). Working closely with Dr Alain Aurias' lab at the Curie Institute, we have shown that MFH comprise two groups with strikingly different genetics and prognosis. The good prognosis group, dedifferentiated liposarcomas, is characterised by amplification of MDM2, CDK4 and genes in the JNK pathway. Patients with these amplicons in their tumours have a 5 year metastasis-free survival rate of 80%, compared with only 50% when tumours lack these changes.

We now have at our disposal BAC and Affymetrix DNA copy number and gene expression data from over 500  sarcomas. This places us in a uniquely strong position to explore sarcoma genetics and tumour biology. In addition to identifying new sarcoma oncogenes, we have established a prognostic gene expression signature, called CINSARC for Complexity INdex in SARComas. Most of the 67 genes in the signature are implicated in mitosis and chromosome management. CINSARC predicts the development of metastases both in the training set, from which it was derived (multivariate hazard ratio 3.7), and in an independent validation set containing 67 sarcomas (multivariate hazard ratio 2.7). It substantially outperforms the existing sarcoma grading system and also predicts the outcome of patients with gastrointestinal stromal tumours, breast carcinomas and lymphomas. Application of the signature will permit more selective use of chemotherapy for patients with sarcomas, leading to decreased iatrogenic morbidity and improved outcomes for individual patients.

To explore the function of candidate new oncogenes and define the contribution of specific genes in the CINSARC signature, we are establishing human cell lines from all sarcomas resected at the Bergonié Institute. These cell lines are characterised in detail to identify the underlying genetic lesions, and followed by CGH every 10 passages to identify and avoid cell culture artefacts. These cell lines constitute a unique resource which we use for RNA interference and classic structure-function studies to test the role of individual genes, in particular in the response of sarcomas to potential new drug treatments.

Publications

Chibon F. Cancer gene expression signatures - The rise and fall? Eur J Cancer. 2013 Mar 13

Lagarde P, Przybyl J, Brulard C, Pérot G, Pierron G, Delattre O, Sciot R, Wozniak A, Schöffski P, Terrier P, Neuville A, Coindre JM, Italiano A, Orbach D, Debiec-Rychter M, Chibon F. Chromosome instability accounts for reverse metastatic outcomes of pediatric and adult synovial sarcomas. J Clin Oncol Published Ahead of Print on January 14, 2013

A Italiano, P Lagarde, C Brulard, P Terrier, M Laë, B Marques, D Ranchere-Vince, J-J Michels, M Trassard, A Cioffi, S Piperno-Neumann, C Chevreau, J-Y Blay, C Delcambre, N Isambert, N Penel, J-O Bay, S Bonvalot, A Le Cesne, J-M Coindre, F Chibon. Genetic Profiling Identifies Two Classes of Soft-Tissue Leiomyosarcomas with Distinct Clinical Characteristics. Clin Cancer Res Published Ahead of Print January 17, 2013.

Pérot G, Croce S, Ribeiro A, Lagarde P, Velasco V, Neuville A, Coindre JM, Stoeckle E, Floquet A, Macgrogan G, Chibon F (2012). MED12 Alterations in Both Human Benign and Malignant Uterine Soft Tissue Tumors. PLoS One. 7(6):e40015.

Lagarde P, Pérot G, Kauffmann A, Brulard C, Dapremont V, Hostein I, Neuville A, Wozniak A, Sciot R, Schöffski P, Aurias A, Coindre JM, Debiec-Rychter M, Chibon F. Mitotic checkpoints and chromosome instability are strong predictors of clinical outcome in Gastrointestinal Stromal Tumors. Clin Cancer Research 2011 Dec 13

Chibon F, Lagarde P, Salas S, Pérot G, Brouste V, Tirode F, Lucchesi C, Aurélien de Reynies, Audrey Kauffmann, Bui B, Collin F, Guillou L, Terrier P, Axel Le Cesne, Sylvie Bonvalot, Vince-Ranchère D, Jean-Yves Blay, Françoise Collin, Leroux A, Coindre JM and Aurias A. Prediction of clinical outcome in sarcomas and multiple types of cancer based on CINSARC, a gene-expression signature related to genome complexity. Nat. Med. 2010 jul;16(7) :781-787.

Dreux N, Marty M, Chibon F, Vélasco V, Hostein I, Ranchère-Vince D, Terrier P, Coindre JM. Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases. Mod Pathol. 2010 Sep 10.

Hélias-Rodzewicz Z, Pérot G, Chibon F, Ferreira C, Lagarde P, Terrier P, Coindre J.M., Aurias A. YAP1 and VGLL3, encoding two cofactors of TEAD transcription factors, are amplified and overexpressed in a subset of soft tissue sarcomas. Genes Chromosomes Cancer. 2010 Sep 14.

Pérot G, Chibon F, Montero A, Lagarde P, de Thé H, Terrier P, Guillou L, Ranchère D, Coindre JM and Aurias A. Constant p53 pathway inactivation in a large series of soft tissue sarcomas with complex genetics. American Journal of Pathology. 2010. 177, No. 4, October.

Chibon F, Salas S, Noguchi T, Terrier P, Ranchere-Vince D, Lagarde P, Benard J, Forget S, Bonvalot S, Guillou L, Leroux A, Mechine-Neuville A, Schöffski P, Laë M, Collin F, Verola O, Carbonnelle A, Vescovo L, Bui B, Brouste V, Sobol H, Aurias A and Coindre JM. Molecular characterization by array comparative genomic hybridization (array CGH) and DNA sequencing of 194 desmoid tumors. Genes Chromosomes Cancer.  2010 Jun;49(6):560-8.

Chibon, F., O. Mariani, J. Derre, A. Mairal, J. M. Coindre, L. Guillou, X. Sastre, F. Pedeutour and A. Aurias. "ASK1 (MAP3K5) as a potential therapeutic target in malignant fibrous histiocytomas with 12q14-q15 and 6q23 amplifications." Genes Chromosomes Cancer . 2004. 40: 32-7.

Chibon, F., O. Mariani, J. Derre, S. Malinge, J. M. Coindre, L. Guillou, R. Lagace and A. Aurias (). "A subgroup of malignant fibrous histiocytomas is associated with genetic changes similar to those of well-differentiated liposarcomas." Cancer Genet Cytogenet 2002.139: 24-9.

Chibon, F., A. Mairal, P. Freneaux, P. Terrier, J. M. Coindre, X. Sastre and A. Aurias. "The RB1 gene is the target of chromosome 13 deletions in malignant fibrous histiocytoma." Cancer Res.  2000.  60: 6339-45.

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