Diversité et plasticité des tumeurs de l’enfant

Publications de l’équipe

Année de publication : 2010

Nadège Gruel, Carlo Lucchesi, Virginie Raynal, Manuel J Rodrigues, Gaëlle Pierron, Rémi Goudefroye, Paul Cottu, Fabien Reyal, Xavier Sastre-Garau, Alain Fourquet, Olivier Delattre, Anne Vincent-Salomon (2010 Jun 24)

Lobular invasive carcinoma of the breast is a molecular entity distinct from luminal invasive ductal carcinoma.

European journal of cancer (Oxford, England : 1990) : 2399-407 : DOI : 10.1016/j.ejca.2010.05.013 En savoir plus
Résumé

In order to get insight into the molecular alterations of invasive lobular carcinoma (ILC), comparative genomic hybridisation array and transcriptomic analyses of a series of 62 oestrogens-positive (ER) invasive tumours [21 ILC and 41 invasive ductal carcinomas (IDC)] were performed. ILC and IDC shared highly recurrent regions of gains (1q12-q44(+) in more than 60% of the cases, 16pter-p11.2(+) in 45% and 63% of ILC and IDC, respectively) and losses (16q11.2-q24.2(-) in 84% of ILC and 67.5% of IDC and 17pter-p12(-) in 50% of ILC and IDC). However, ILC genomic signature was characterised by significantly more frequent losses of 13q21.33-q31.3 region (46.5%) and 22q11.23-q12.1 region (50%) whereas IDC showed significantly more frequent losses of 11q23.1-q23.2 region (in 44% of IDC). Nine different regions of high level amplifications were found in 38% of ILC (8/21 cases). Localised on chromosome 11 (11q13.2 region), the most frequent region of amplification encompassing the CCND1 and FGF3 genes was observed in five different ILC. Unsupervised hierarchical clustering of transcriptomic data showed that ILC and IDC clustered apart. Genes involved in cell adhesion, cell communication and trafficking, extra cellular matrix-interaction pathways or cell mobility contributed to this clustering. Despite these differences, the overall clinical outcome of ILC was identical to that of IDC. This molecular study highlights that lobular and oestrogens-positive ductal invasive carcinomas share common genomic alterations but that ILC present some specific molecular alterations. These molecular specificities should help with the identification of new therapeutic targets for ILC patients.

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Gudrun Schleiermacher, Isabelle Janoueix-Lerosey, Agnès Ribeiro, Jerzy Klijanienko, Jérôme Couturier, Gaëlle Pierron, Véronique Mosseri, Alexander Valent, Nathalie Auger, Dominique Plantaz, Hervé Rubie, Dominique Valteau-Couanet, Franck Bourdeaut, Valérie Combaret, Christophe Bergeron, Jean Michon, Olivier Delattre (2010 Jun 1)

Accumulation of segmental alterations determines progression in neuroblastoma.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology : 3122-30 : DOI : 10.1200/JCO.2009.26.7955 En savoir plus
Résumé

Neuroblastoma is characterized by two distinct types of genetic profiles, consisting of either numerical or segmental chromosome alterations. The latter are associated with a higher risk of relapse, even when occurring together with numerical alterations. We explored the role of segmental alterations in tumor progression and the possibility of evolution from indolent to aggressive genomic types.

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Daniel Williamson, Edoardo Missiaglia, Aurélien de Reyniès, Gaëlle Pierron, Benedicte Thuille, Gilles Palenzuela, Khin Thway, Daniel Orbach, Marick Laé, Paul Fréneaux, Kathy Pritchard-Jones, Odile Oberlin, Janet Shipley, Olivier Delattre (2010 Mar 31)

Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology : 2151-8 : DOI : 10.1200/JCO.2009.26.3814 En savoir plus
Résumé

To determine whether the clinical and molecular biologic characteristics of the alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) subtypes have relevance independent of the presence or absence of the PAX/FOXO1 fusion gene.

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Année de publication : 2009

Franck Bourdeaut, Isabelle Janoueix-Lerosey, Carlo Lucchesi, Régine Paris, Agnès Ribeiro, Loïc de Pontual, Jeanne Amiel, Stanislas Lyonnet, Gaëlle Pierron, Jean Michon, Michel Peuchmaur, Olivier Delattre (2009 Sep 22)

Cholinergic switch associated with morphological differentiation in neuroblastoma.

The Journal of pathology : 463-72 : DOI : 10.1002/path.2614 En savoir plus
Résumé

The morphology of malignant cells distinguishes between undifferentiated, poorly differentiated and differentiating neuroblastomas and constitutes a strong prognostic factor. Spontaneous or treatment-induced maturation characterizes a subset of neuroblastomas. It constitutes the basis of retinoic acid treatment to improve survival in aggressive neuroblastomas. However, the molecular events that drive differentiation are poorly understood. In the present study we have investigated the relationships between gene expression profiles and differentiation criteria in stroma-poor neuroblastomas. This study included three undifferentiated (UN), 20 poorly differentiated (PDN) and 11 differentiating (DN) neuroblastomas. These groups could be clearly separated using unsupervised clustering methods, which further enabled a major classification impact of genes involved in neural development, differentiation and function to be identified. UNs are characterized by high ASCL1, high PHOX2B, low GATA2, low TH and low DBH expressions. Most PDNs harbour a clear adrenergic phenotype, even in the presence of missense PHOX2B mutations. Finally, all DN tumours demonstrate cholinergic features. Depending upon their association with adrenergic characteristics, this enables dual ‘cholinergic/adrenergic’ and ‘fully cholinergic’ neuroblastomas to be defined. This suggests that the cholinergic switch, a final specification process that occurs physiologically in a minority of sympathetic neurons, is a critical step of differentiation in some neuroblastic tumours. This switch is associated with a down regulation of DBH that is apparently not strictly dependent upon PHOX2B. Conversely, GATA2 and TFAP2B may play critical roles in maintaining adrenergic features in poorly differentiated tumours.

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Isabelle Janoueix-Lerosey, Gudrun Schleiermacher, Evi Michels, Véronique Mosseri, Agnès Ribeiro, Delphine Lequin, Joëlle Vermeulen, Jérôme Couturier, Michel Peuchmaur, Alexander Valent, Dominique Plantaz, Hervé Rubie, Dominique Valteau-Couanet, Caroline Thomas, Valérie Combaret, Raphaël Rousseau, Angelika Eggert, Jean Michon, Frank Speleman, Olivier Delattre (2009 Jan 28)

Overall genomic pattern is a predictor of outcome in neuroblastoma.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology : 1026-33 : DOI : 10.1200/JCO.2008.16.0630 En savoir plus
Résumé

For a comprehensive overview of the genetic alterations of neuroblastoma, their association and clinical significance, we conducted a whole-genome DNA copy number analysis.

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Franck Bourdeaut, Emilie de Carli, Sandra Timsit, Carole Coze, Pascal Chastagner, Sabine Sarnacki, Olivier Delattre, Michel Peuchmaur, Hervé Rubie, Jean Michon, (2009 Jan 15)

VIP hypersecretion as primary or secondary syndrome in neuroblastoma: A retrospective study by the Société Française des Cancers de l’Enfant (SFCE).

Pediatric blood & cancer : 585-90 : DOI : 10.1002/pbc.21912 En savoir plus
Résumé

Neuroblastic tumors (NTs) are occasionally associated with watery diarrhea, due to Vasoactive Intestinal Peptide (VIP) secretion. Most reports are single cases and suggest a great homogeny within this sub-group of NTs.

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Année de publication : 2008

Franck Tirode, Olivier Delattre (2008 Dec 17)

[Stem cells and connective-tissue tumors: Ewing’s sarcoma].

Annales de pathologie : S33-4 : DOI : 10.1016/j.annpat.2008.09.006 En savoir plus
Résumé

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Julie Caramel, Frédérique Quignon, Olivier Delattre (2008 Aug 5)

RhoA-dependent regulation of cell migration by the tumor suppressor hSNF5/INI1.

Cancer research : 6154-61 : DOI : 10.1158/0008-5472.CAN-08-0115 En savoir plus
Résumé

Malignant rhabdoid tumors (MRT) are extremely aggressive pediatric tumors caused by the inactivation of the hSNF5/INI1 tumor suppressor gene, which encodes a core member of the SWI/SNF chromatin remodeling complex. Roles for hSNF5/INI1 in cell cycle and differentiation have been documented. Based on the observation that MRTs are highly invasive, we investigated a role for hSNF5/INI1 in cell migration. MRT cell lines exhibit high migration properties that are dramatically reduced upon hSNF5/INI1 expression. This effect is associated with the disorganization of the actin stress fiber network and is mediated by the inhibition of the activity of the small GTPase RhoA, through a nuclear, SWI/SNF-dependent transcriptional mechanism. We further show that the knockdown of hSNF5/INI1 in epithelial 293T or MCF7 cells results in increased cell size, loss of cell-cell adhesions, and enhanced migration, associated with an increased RhoA activity. Finally, we show that the SNF5 homology domain is required for hSNF5/INI1-mediated inhibition of migration, and that a missense mutation (S284L) associated with cancer is sufficient to impair hSNF5/INI1 function in migration. We conclude that the inhibition of migration is another crucial tumor suppressor function of hSNF5/INI1, in addition to its previously described functions in proliferation and differentiation, and that its loss-of-function in MRTs may account for the high invasiveness and metastatic potential of these tumors.

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Anne Fix, Carlo Lucchesi, Agnès Ribeiro, Delphine Lequin, Gaëlle Pierron, Gudrun Schleiermacher, Olivier Delattre, Isabelle Janoueix-Lerosey (2008 Jun 17)

Characterization of amplicons in neuroblastoma: high-resolution mapping using DNA microarrays, relationship with outcome, and identification of overexpressed genes.

Genes, chromosomes & cancer : 819-34 : DOI : 10.1002/gcc.20583 En savoir plus
Résumé

Somatically acquired chromosomal imbalances are a key feature of neuroblastoma, a heterogeneous pediatric solid tumor. Among these alterations, genomic amplification targeting the MYCN oncogene and observed in about 25-30% of the cases, strongly correlates with advanced stage and poor outcome. In this work, we have used BAC and SNP arrays as well as gene expression arrays to characterize amplifications in neuroblastoma. Eighty-eight distinct BACs defining high-level amplification events were identified in 65 samples, including 43 tumors and 22 cell lines. Although the highest recurrence was observed on chromosome 2, clones on chromosomes 8, 12, 16, and 17 also revealed genomic amplification in several samples. A detailed analysis of the 2p22-2p25 MYCN containing region indicated highly complex patterns in a number of cases. Coamplifications involving MYCN and other regions were explored by FISH in three cell lines. High-resolution arrays then allowed us to further refine the mapping of 25 amplicons in 19 samples, either reducing the size of a single continuous amplicon or increasing the complexity by highlighting multiple noncontiguous regions of amplification. Combined analysis of gene expression profiling and array-CGH data indicated that 12 to 25% of the genes that are targeted by genomic amplification are actually over-expressed in tumor cells, several of them having already been implicated in cancer. Finally, our results suggest that the presence of amplicons localized outside of chromosome 2, in addition to MYCN amplification, may be linked to a particularly severe outcome in neuroblastoma patients.

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Franck Bourdeaut, Paul Fréneaux, Bénédicte Thuille, Christophe Bergeron, Valérie Laurence, Laurence Brugières, Cécile Vérité, Jean Michon, Olivier Delattre, Daniel Orbach (2008 May 29)

Extra-renal non-cerebral rhabdoid tumours.

Pediatric blood & cancer : 363-8 : DOI : 10.1002/pbc.21632 En savoir plus
Résumé

Rhabdoid tumours (RTs) are aggressive malignancies of childhood, mainly occurring in the kidney and brain. We describe a national multi-centre retrospective analysis of extra-renal non-cranial RTs (ERRTs).

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Isabelle Janoueix-Lerosey, Delphine Lequin, Laurence Brugières, Agnès Ribeiro, Loïc de Pontual, Valérie Combaret, Virginie Raynal, Alain Puisieux, Gudrun Schleiermacher, Gaëlle Pierron, Dominique Valteau-Couanet, Thierry Frebourg, Jean Michon, Stanislas Lyonnet, Jeanne Amiel, Olivier Delattre (2008 May 26)

Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.

Nature : 967-70 : DOI : 10.1038/nature07398 En savoir plus
Résumé

Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. It usually occurs sporadically but familial cases are observed, with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments.

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Anne Vincent-Salomon, Carlo Lucchesi, Nadège Gruel, Virginie Raynal, Gaëlle Pierron, Rémi Goudefroye, Fabien Reyal, François Radvanyi, Rémy Salmon, Jean-Paul Thiery, Xavier Sastre-Garau, Brigitte Sigal-Zafrani, Alain Fourquet, Olivier Delattre, (2008 Apr 3)

Integrated genomic and transcriptomic analysis of ductal carcinoma in situ of the breast.

Clinical cancer research : an official journal of the American Association for Cancer Research : 1956-65 : DOI : 10.1158/1078-0432.CCR-07-1465 En savoir plus
Résumé

To gain insight into genomic and transcriptomic subtypes of ductal carcinomas in situ of the breast (DCIS).

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Année de publication : 2007

Franck Bourdeaut, Anne Guiochon-Mantel, Monique Fabre, Hélène Martelli, Catherine Patte, Gilda Porta, Olivier Bernard, Olivier Delattre, Emmanuel Jacquemin (2007 Jun 23)

Alagille syndrome and nephroblastoma: Unusual coincidence of two rare disorders.

Pediatric blood & cancer : 908-11 En savoir plus
Résumé

Alagille syndrome is a rare developmental disorder combining bile duct paucity, congenital cardiopathy, facial dysmorphy, vertebrae defects, and ocular abnormalities, and frequent renal abnormalities. It does not usually predispose to malignancies. Nephroblastoma has been observed in many developmental disorders, but never in Alagille syndrome. We report two original cases of nephroblastoma associated to Alagille syndrome. We identified a new V136G JAG1 missense mutation in one patient and a constitutional deletion of 20p12 in the other. In one nephroblastoma an additional somatic 1p36 deletion was present. The link between Alagille syndrome, JAG1 alterations and nephroblastoma is discussed.

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Franck Tirode, Karine Laud-Duval, Alexandre Prieur, Bruno Delorme, Pierre Charbord, Olivier Delattre (2007 May 8)

Mesenchymal stem cell features of Ewing tumors.

Cancer cell : 421-9 En savoir plus
Résumé

The cellular origin of Ewing tumor (ET), a tumor of bone or soft tissues characterized by specific fusions between EWS and ETS genes, is highly debated. Through gene expression analysis comparing ETs with a variety of normal tissues, we show that the profiles of different EWS-FLI1-silenced Ewing cell lines converge toward that of mesenchymal stem cells (MSC). Moreover, upon EWS-FLI1 silencing, two different Ewing cell lines can differentiate along the adipogenic lineage when incubated in appropriate differentiation cocktails. In addition, Ewing cells can also differentiate along the osteogenic lineage upon long-term inhibition of EWS-FLI1. These in silico and experimental data strongly suggest that the inhibition of EWS-FLI1 may allow Ewing cells to recover the phenotype of their MSC progenitor.

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Odette Mariani, Caroline Brennetot, Jean-Michel Coindre, Nadège Gruel, Carine Ganem, Olivier Delattre, Marc-Henri Stern, Alain Aurias (2007 Apr 10)

JUN oncogene amplification and overexpression block adipocytic differentiation in highly aggressive sarcomas.

Cancer cell : 361-74 En savoir plus
Résumé

The human oncogene JUN encodes a component of the AP-1 complex and is consequently involved in a wide range of pivotal cellular processes, including cell proliferation, transformation, and apoptosis. Nevertheless, despite extensive analyses of its functions, it has never been directly involved in a human cancer. We demonstrate here that it is highly amplified and overexpressed in undifferentiated and aggressive human sarcomas, which are blocked at an early step of adipocyte differentiation. We confirm by cellular and xenograft mouse models recapitulating these sarcoma genetics that the failure to differentiate is dependent upon JUN amplification/overexpression.

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