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Le Touquet – Paris-Plage, France

Travert M.,French Institute of Health and Medical Research | Travert M.,UniversiteParis Est | Huang Y.,French Institute of Health and Medical Research | Huang Y.,UniversiteParis Est | And 16 more authors.
Blood | Year: 2012

The pathogenesis of hepatosplenic T-cell lymphoma (HSTL), a rare entity mostly derived from γδ T cells and usually with a fatal outcome, remains largely unknown. In this study, HSTL samples (7γδ and 2αβ) and the DERL2 HSTL cell line were subjected to combined gene-expression profiling and array-based comparative genomic hybridization. Compared with other T-cell lymphomas, HSTL had a distinct molecular signature irrespective of TCR cell lineage. Compared with peripheral T-cell lymphoma, not otherwise specified and normal γδ T cells, HSTL overexpressed genes encoding NK-cell-associated molecules, oncogenes (FOS and VAV3), the sphingosine-1-phosphatase receptor 5 involved in cell trafficking, and the tyrosine kinase SYK, whereas the tumor-suppressor gene AIM1 (absent in melanoma 1) was among the most downexpressed. We found highly methylated CpG islands of AIM1 in DERL2 cells, and decitabine treatment induced a significant increase in AIM1 transcripts. Syk was present in HSTL cells and DERL2 cells contained phosphorylated Syk and were sensitive to a Syk inhibitor in vitro. Genomic profiles confirmed recurrent isochromosome 7q (n = 6/9) without alterations at the SYK and AIM1 loci. Our results identify a distinct molecular signature for HSTL and highlight oncogenic pathways that offer rationale for exploring new therapeutic options such as Syk inhibitors and demethylating agents. © 2012 by The American Society of Hematology.

Karsenty S.,University of Nantes | Hirsch A.,Ligue Nationale Contre le Cancer
Bulletin Epidemiologique Hebdomadaire | Year: 2010

Background - The first French program against cancer was carried out from 2003 to 2007. It included many important legal measures to reduce tobacco smoking. Three of them, increasing tobacco prices, restricting youth access and smoking in public areas, raised the question of their possible assessment through various data gathered from 1999 to 2008. Methods - Several data sources and linked publications were examined. Legal sales in France, estimations of foreign tobacco products purchases, prevalences in adults and youth could sometimes, but not always, allow longitudinal analysis. Results - Increasing tobacco prices induced a 31% drop in domestic legal sales adjusted for population size between 2002 and 2008. Foreign tobacco products would account for 12% to 20% of the total consumption depending on the sources, reckonings and year. Daily smoking prevalence in people aged 15-75 decreased by 12% between 1999 and 2005 without trend reversal later on. In youths aged 15 and 16 daily smoking prevalence decreased by 45% between 1999 and 2007. Discussion-conclusion - Estimating the importance of purchases out of France and their trends is not possible due to the lack of reliable and published data. Trends in total population smoking prevalence can fit with the domestic sales data but a new analysis is needed when new data are available in 2010. The cancer plan has revealed to be a succcess in terms of trends in adolescent smoking.

Cairo S.,Institute Pasteur Paris | Cairo S.,French Institute of Health and Medical Research | Wang Y.,Vaccine Research Institute of San Diego | Wang Y.,University of California at Irvine | And 14 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Myc activation has been implicated in the pathogenesis ofhepatoblastoma (HB), a rare embryonal neoplasm derived from liver progenitor cells. Here, microRNA (miR) expression profiling of 65 HBs evidenced differential patterns related to developmental stage and Myc activity. Undifferentiated aggressive HBs overexpressed the miR-371-3 cluster with concomitant down-regulation of the miR-100/let-7a-2/miR-125b-1 cluster, evoking an ES cell expression profile. ChIP and Myc inhibition assays in hepatoma cells demonstrated that both miR clusters are regulated by Myc in an opposite manner. We show that the two miR clusters exert antagonistic effects on cell proliferation and tumorigenicity. Moreover, their combined deregulation cooperated in modulating the hepatic tumor phenotype, implicating stem cell-like regulation of Myc-dependent miRs in poorly differentiated HBs. Importantly, a four-miR signature representative of these clusters efficiently stratified HB patients, and when applied to 241 hepatocellular carcinomas (HCCs), it identified invasive tumors with a poor prognosis. Our data argue that Myc-driven reprogramming of miR expression patterns contributes to the aggressive phenotype of liver tumors originating from hepatic progenitor cells.

Bisig B.,University of Lausanne | Bisig B.,University of Liege | de Reynies A.,Ligue Nationale Contre le Cancer | Bonnet C.,CHU Sart Tilman | And 10 more authors.
Haematologica | Year: 2013

Peripheral T-cell lymphoma, not otherwise specified is a heterogeneous group of aggressive neoplasms with indistinct borders. By gene expression profiling we previously reported unsupervised clusters of peripheral T-cell lymphomas, not otherwise specified correlating with CD30 expression. In this work we extended the analysis of peripheral T-cell lymphoma molecular profiles to prototypical CD30+ peripheral T-cell lymphomas (anaplastic large cell lymphomas), and validated mRNA expression profiles at the protein level. Existing transcriptomic datasets from peripheral T-cell lymphomas, not otherwise specified and anaplastic large cell lymphomas were reanalyzed. Twenty-one markers were selected for immunohistochemical validation on 80 peripheral T-cell lymphoma samples (not otherwise specified, CD30+ and CD30-; anaplastic large cell lymphomas, ALK+ and ALK-), and differences between subgroups were assessed. Clinical follow-up was recorded. Compared to CD30- tumors, CD30+ peripheral T-cell lymphomas, not otherwise specified were significantly enriched in ALK- anaplastic large cell lymphoma-related genes. By immunohistochemistry, CD30+ peripheral T-cell lymphomas, not otherwise specified differed significantly from CD30- samples [down-regulated expression of T-cell receptor-associated proximal tyrosine kinases (Lck, Fyn, Itk) and of proteins involved in T-cell differentiation/activation (CD69, ICOS, CD52, NFATc2); upregulation of JunB and MUM1], while overlapping with anaplastic large cell lymphomas. CD30- peripheral T-cell lymphomas, not otherwise specified tended to have an inferior clinical outcome compared to the CD30+ subgroups. In conclusion, we show molecular and phenotypic features common to CD30+ peripheral T-cell lymphomas, and significant differences between CD30- and CD30+ peripheral T-cell lymphomas, not otherwise specified, suggesting that CD30 expression might delineate two biologically distinct subgroups. © 2013 Ferrata Storti Foundation.

De Reynies A.,Ligue Nationale Contre le Cancer | Jaurand M.-C.,French Institute of Health and Medical Research | Jaurand M.-C.,University Paris Diderot | Renier A.,French Institute of Health and Medical Research | And 23 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Despite research efforts to develop more effective diagnostic and therapeutic approaches, malignant pleural mesothelioma (MPM) prognosis remains poor. The assessment of tumor response to therapy can be improved by a deeper phenotypical classification of the tumor, with emphasis on its clinicobiological heterogeneity. The identification of molecular profiles is a powerful approach to better define MPM subclasses and targeted therapies. Experimental Design: Molecular subclasses were defined by transcriptomic microarray on 38 primary MPM cultures. A three-gene predictor, identified by quantitative reverse transcription PCR, was used to classify an independent series of 108 frozen tumor samples. Gene mutations were determined in BAP1, CDKN2A, CDKN2B, NF2, and TP53. Epithelial-to-mesenchymal transition (EMT) markers were studied at the mRNA and protein levels. Results: Unsupervised hierarchical clustering on transcriptomic data defined two robustMPMsubgroups (C1 and C2), closely related to prognosis and partly to histologic subtypes. All sarcomatoid/desmoplastic MPM were included in the C2 subgroup. Epithelioid MPM were found in both subgroups, with a worse survival prognosis in the C2 subgroup. This classification and its association with histologic subtypes and survival were validated in our independent series using the three-gene predictor. Similar subgroups were found after classification of other MPM series from transcriptomic public datasets. C1 subgroup exhibited more frequent BAP1 alterations. Pathway analysis revealed that EMT was differentially regulated between MPM subgroups. C2 subgroup is characterized by a mesenchymal phenotype. Conclusions: A robust classification of MPM that defines two subgroups of epithelioid MPM, characterized by different molecular profiles, gene alterations, and survival outcomes, was established. © 2014 AACR.

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