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Dive into the research topics where Gaëlle Pérot is active.

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Featured researches published by Gaëlle Pérot.


Nature Medicine | 2010

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

Frédéric Chibon; Pauline Lagarde; Sébastien Salas; Gaëlle Pérot; Véronique Brouste; Franck Tirode; Carlo Lucchesi; Aurélien de Reyniès; Audrey Kauffmann; B. Bui; Philippe Terrier; Sylvie Bonvalot; Axel Le Cesne; Dominique Vince-Ranchère; Jean-Yves Blay; Françoise Collin; Louis Guillou; Agnès Leroux; Jean-Michel Coindre; Alain Aurias

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.


Journal of Clinical Oncology | 2013

Chromosome Instability Accounts for Reverse Metastatic Outcomes of Pediatric and Adult Synovial Sarcomas

Pauline Lagarde; Joanna Przybyl; Céline Brulard; Gaëlle Pérot; Gaëlle Pierron; Olivier Delattre; Raf Sciot; Agnieszka Wozniak; Patrick Schöffski; Philippe Terrier; Agnès Neuville; Jean-Michel Coindre; Antoine Italiano; Daniel Orbach; Maria Debiec-Rychter; Frédéric Chibon

PURPOSE Synovial sarcoma (SS) occurs in both children and adults, although metastatic events are much more common in adults. Whereas the importance of the t(X;18) translocation in SS oncogenesis is well established, the genetic basis of SS metastasis is still poorly understood. We recently reported expression (CINSARC; Complexity Index in Sarcoma) and Genomic Index prognostic signatures related to chromosome integrity in sarcomas and GI stromal tumors. Here we investigate whether these signatures can also predict outcomes in SS. PATIENTS AND METHODS One hundred patients who had primary untreated SS tumors were selected for expression and genomic profiling in a training/validation approach. RESULTS CINSARC and Genomic Index have strong independent and validated prognostic values (P < .001). By comparing expression profiles of tumors with or without metastasis, 14 genes that are common to the CINSARC signature were identified, and the two top-ranked genes, KIF14 and CDCA2, were validated as prognostic markers in an independent cohort. Comparing genomic profiles of adult versus pediatric SS, we show that metastasis is associated with genome complexity in both situations and that the adult genome is more frequently rearranged. Accordingly, pediatric patients with an even genomic profile do not develop metastasis. CONCLUSION Metastasis development in SS is strongly associated with chromosome complexity, and CINSARC and Genomic Index are validated independent prognostic factors. The differences in metastasis frequency between adults and children are associated with genome instability, which is much more frequent in adults. Genomic Index is potentially the best overall biomarker and clearly the most clinically relevant, considering that genome profiling from formalin-fixed samples is already used in pathology.


Clinical Cancer Research | 2012

MITOTIC CHECKPOINTS AND CHROMOSOME INSTABILITY ARE STRONG PREDICTORS OF CLINICAL OUTCOME IN GASTROINTESTINAL STROMAL TUMORS.

Pauline Lagarde; Gaëlle Pérot; Audrey Kauffmann; Céline Brulard; Valérie Dapremont; Isabelle Hostein; Agnès Neuville; Agnieszka Wozniak; Raf Sciot; Patrick Schöffski; Alain Aurias; Jean-Michel Coindre; Maria Debiec-Rychter; Frédéric Chibon

Purpose: The importance of KIT and PDGFRA mutations in the oncogenesis of gastrointestinal stromal tumors (GIST) is well established, but the genetic basis of GIST metastasis is poorly understood. We recently published a 67 gene expression prognostic signature related to genome complexity (CINSARC for Complexity INdex in SARComas) and asked whether it could predict outcome in GISTs. Experimental Design: We carried out genome and expression profiling on 67 primary untreated GISTs. Results: We show and validate here that it can predict metastasis in a new data set of 67 primary untreated GISTs. The gene whose expression was most strongly associated with metastasis was AURKA, but the AURKA locus was not amplified. Instead, we identified deletion of the p16 (CDKN2A) and retinoblastoma (RB1) genes as likely causal events leading to increased AURKA and CINSARC gene expression, to chromosome rearrangement, and ultimately to metastasis. On the basis of these findings, we established a Genomic Index that integrates the number and type of DNA copy number alterations. This index is a strong prognostic factor in GISTs. We show that CINSARC class, AURKA expression, and Genomic Index all outperform the Armed Forces Institute of Pathology (AFIP) grading system in determining the prognosis of patients with GISTs. Interestingly, these signatures can identify poor prognosis patients in the group classified as intermediate-risk by the AFIP classification. Conclusions: We propose that a high Genomic Index determined by comparative genomic hybridization from formalin-fixed, paraffin-embedded samples could be used to identify AFIP intermediate-risk patients who would benefit from imatinib therapy. Clin Cancer Res; 18(3); 826–38. ©2011 AACR.


Genes, Chromosomes and Cancer | 2010

YAP1 and VGLL3, encoding two cofactors of TEAD transcription factors, are amplified and overexpressed in a subset of soft tissue sarcomas.

Zofia Hélias-Rodzewicz; Gaëlle Pérot; Frédéric Chibon; Céline Ferreira; Pauline Lagarde; Philippe Terrier; Jean-Michel Coindre; Alain Aurias

In a series of 404 adult soft tissue sarcomas, analyzed by array‐CGH, we have observed in approximately 10% of them a genomic amplification of either chromosome bands 11q22 or 3p12. These two amplicons likely target the YAP1 and VGLL3 genes, respectively. Both genes encode proteins that are cofactors of the TEAD family of transcription factors. Very good correlations between amplification and expression levels were observed. Welch test analyses of transcriptome data demonstrate that tumors with amplicons share a large set of upregulated and downregulated genes. Inhibition of YAP1 and VGLL3 in cell lines with these amplifications/overexpressions leads to similar phenotypes: decrease of proliferation rate, and to a lesser extent decrease of migration properties. These data, and the fact that these amplicons are observed either in dedifferentited liposarcomas or in undifferentiated pleomorphic sarcomas, suggest that these genetics events could be involved in oncogenesis and progression of soft tissue sarcomas.


The Journal of Pathology | 2011

New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics†

Laure Gibault; Gaëlle Pérot; Frédéric Chibon; Sarah Bonnin; Pauline Lagarde; Philippe Terrier; Jean-Michel Coindre; Alain Aurias

Adult soft tissue sarcomas (STS) are rare tumours of mesenchymal lineage. Based on cytogenetic and comparative genomic hybridization (CGH) data, they can be divided into ‘STS with simple genomics’, displaying a characteristic genetic alteration, and ‘STS with complex genomics’ (SCG), where multiple genomic alterations occur. This latter group is mostly composed of leiomyosarcomas (LMS) and pleiomorphic undifferentiated tumours previously labelled as ‘malignant fibrous histiocytomas’ (MFH), corresponding in fact to myxofibrosarcomas (MFS), pleiomorphic liposarcomas/rhabdomyosarcomas (P‐LPS, P‐RMS), and undifferentiated pleiomorphic sarcomas (UPS). Their pathobiology is still not well understood, leading to challenges in diagnosis and therapeutic management. We report here a comprehensive study encompassing array‐CGH and transcriptome analysis data of a large series of 160 SCG. Non‐supervised clustering of transcriptome data led to the identification of five groups of tumours, one of them (group A) corresponding to well‐differentiated LMS and the other four (B–E) to ‘MFH’ and poorly differentiated LMS. Welch analysis of transcriptome data in these groups allowed us to retrieve several genes of potential interest. Among them, RB1 alteration is a constant thread in SCG, often associated with RBL2 loss. PTEN tumour suppressor deletion would also stand out as a major recurrent event, especially in groups A, C, and D. The WNT canonical pathway could be potentially involved, as demonstrated by up‐regulation of one of its inhibitors, DKK1, in groups D and E, whereas DKK1 is significantly down‐regulated in groups A, B, and C. These data suggest a very complex interplay between pathways downstream of PTEN and the WNT canonical pathway, providing new hints about SCG pathobiology and their potential therapeutic targets. Copyright


American Journal of Pathology | 2010

Constant p53 Pathway Inactivation in a Large Series of Soft Tissue Sarcomas with Complex Genetics

Gaëlle Pérot; Frédéric Chibon; Audrey Montero; Pauline Lagarde; Philippe Terrier; Louis Guillou; Dominique Ranchère; Jean-Michel Coindre; Alain Aurias

Alterations of the p53 pathway are among the most frequent aberrations observed in human cancers. We have performed an exhaustive analysis of TP53, p14, p15, and p16 status in a large series of 143 soft tissue sarcomas, rare tumors accounting for around 1% of all adult cancers, with complex genetics. For this purpose, we performed genomic studies, combining sequencing, copy number assessment, and expression analyses. TP53 mutations and deletions are more frequent in leiomyosarcomas than in undifferentiated pleomorphic sarcomas. Moreover, 50% of leiomyosarcomas present TP53 biallelic inactivation, whereas most undifferentiated pleomorphic sarcomas retain one wild-type TP53 allele (87.2%). The spectrum of mutations between these two groups of sarcomas is different, particularly with a higher rate of complex mutations in undifferentiated pleomorphic sarcomas. Most tumors without TP53 alteration exhibit a deletion of p14 and/or lack of mRNA expression, suggesting that p14 loss could be an alternative genotype for direct TP53 inactivation. Nevertheless, the fact that even in tumors altered for TP53, we could not detect p14 protein suggests that other p14 functions, independent of p53, could be implicated in sarcoma oncogenesis. In addition, both p15 and p16 are frequently codeleted or transcriptionally co-inhibited with p14, essentially in tumors with two wild-type TP53 alleles. Conversely, in TP53-altered tumors, p15 and p16 are well expressed, a feature not incompatible with an oncogenic process.


Cancer Research | 2009

Strong Smooth Muscle Differentiation Is Dependent on Myocardin Gene Amplification in Most Human Retroperitoneal Leiomyosarcomas

Gaëlle Pérot; Josette Derré; Jean-Michel Coindre; Franck Tirode; Carlo Lucchesi; Odette Mariani; Laure Gibault; Louis Guillou; Philippe Terrier; Alain Aurias

Myocardin (MYOCD), a serum response factor (SRF) transcriptional cofactor, is essential for cardiac and smooth muscle development and differentiation. We show here by array-based comparative genomic hybridization, fluorescence in situ hybridization, and expression analysis approaches that MYOCD gene is highly amplified and overexpressed in human retroperitoneal leiomyosarcomas (LMS), a very aggressive well-differentiated tumor. MYOCD inactivation by shRNA in a human LMS cell line with MYOCD locus amplification leads to a dramatic decrease of smooth muscle differentiation and strongly reduces cell migration. Moreover, forced MYOCD expression in three undifferentiated sarcoma cell lines and in one liposarcoma cell line confers a strong smooth muscle differentiation phenotype and increased migration abilities. Collectively, these results show that human retroperitoneal LMS differentiation is dependent on MYOCD amplification/overexpression, suggesting that in these well-differentiated LMS, differentiation could be a consequence of an acquired genomic alteration. In this hypothesis, these tumors would not necessarily derive from cells initially committed to smooth muscle differentiation. These data also provide new insights on the cellular origin of these sarcomas and on the complex connections between oncogenesis and differentiation in mesenchymal tumors.


Nature Genetics | 2015

Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite

Thomas G. P. Grunewald; Virginie Bernard; Pascale Gilardi-Hebenstreit; Virginie Raynal; Didier Surdez; Marie Ming Aynaud; Olivier Mirabeau; Florencia Cidre-Aranaz; Franck Tirode; Sakina Zaidi; Gaëlle Pérot; Anneliene H. Jonker; Carlo Lucchesi; Marie Cécile Le Deley; Odile Oberlin; Perrine Marec-Berard; Amelie S. Veron; Stéphanie Reynaud; Eve Lapouble; Valentina Boeva; Thomas Rio Frio; Javier Alonso; Smita Bhatia; Gaëlle Pierron; Geraldine Cancel-Tassin; Olivier Cussenot; David G. Cox; Lindsay M. Morton; Mitchell J. Machiela; Stephen J. Chanock

Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1–dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis.


Genes, Chromosomes and Cancer | 2011

The CDKN2A/CDKN2B/CDK4/CCND1 pathway is pivotal in well-differentiated and dedifferentiated liposarcoma oncogenesis: an analysis of 104 tumors.

Caroline Louis-Brennetot; Jean-Michel Coindre; Céline Ferreira; Gaëlle Pérot; Philippe Terrier; Alain Aurias

The MDM2 and CDK4 genes are the main targets of chromosome 12 amplification in well‐differentiated and dedifferentiated liposarcomas. Nevertheless, around 10% of these tumors do not amplify CDK4. To find substitutive alterations of CDK4 amplification, we analyzed a large series of liposarcomas by array‐CGH, real‐time genomic PCR, gene expression array, and real‐time RT‐PCR. We demonstrate that an alteration in the CDKN2A/CDKN2B/CDK4/CCND1 pathway is present in almost all cases without CDK4 amplification, thereby confirming the pivotal role of this pathway in liposarcoma oncogenesis. Moreover, we show that cell cycle and differentiation are driven by a subtle and complex balance between members of this pathway. Finally, we demonstrate that in tumors without amplification/overexpression of CDK4, the chromosome 1q21‐1q23 region is a preferential partner of chromosome 12 amplicon, suggesting that the mechanism of amplification is slightly different in this group of tumors.


Modern Pathology | 2013

Transgelin is a novel marker of smooth muscle differentiation that improves diagnostic accuracy of leiomyosarcomas: a comparative immunohistochemical reappraisal of myogenic markers in 900 soft tissue tumors.

Yves-Marie Robin; Nicolas Penel; Gaëlle Pérot; Agnès Neuville; Valérie Velasco; Dominique Ranchère-Vince; Philippe Terrier; Jean-Michel Coindre

Immunohistochemical use of myogenic markers serves to define smooth or skeletal muscle differentiation in soft tissue tumors. Establishing smooth muscle differentiation in malignant lesions can be challenging in some cases. We immunohistochemically examined 900 soft tissue tumors selected from the French Sarcoma Group’s archived tissue collection, which contains a large number of leiomyosarcomas. The four most widely used smooth muscle diagnostic markers were evaluated (smooth muscle actin, desmin, h-caldesmon and calponin), and compared with a novel marker, transgelin. The diagnostic performance of each marker was statistically assessed in terms of sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and accuracy (A), in leiomyosarcomas versus all other sarcomas including gastrointestinal stromal tumors (GIST), and second in leiomyosarcomas versus specific tumor types. In leiomyosarcomas versus all other sarcomas including GIST, transgelin emerged as the best diagnostic marker (Se: 83%, Sp: 82%, PPV: 67%, NPV: 92%, A: 83%), compared with smooth muscle actin (Se: 75%, Sp: 83, PPV: 66%, NPV: 89%, A: 81%), desmin (Se: 45%, Sp: 88%, PPV: 62%, NPV: 79%, A: 75%), h-caldesmon (Se: 50%, Sp: 90%, PPV: 67%, NPV: 81%, A: 78%) and calponin (Se: 76%, Sp: 70, PPV: 52%, NPV: 87%, A: 71%). In leiomyosarcomas compared with other specific tumor types such as undifferentiated pleomorphic sarcoma and myxofibrosarcoma, the accuracy for transgelin varied from 80 to 87% whereas it was lower for all other markers (between 51 and 80%). These results indicate that transgelin could be used in practice as an additional marker useful for decision making, especially in those tumors with incomplete immunophenotypes.

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Agnès Neuville

Argonne National Laboratory

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