PubMed | University of Lyon, La Renon, Center Paul Strauss, Center Eugene Marquis and 7 more.
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2016
Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3- untranslated regions (3-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1- and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3-UTR and one in BRCA2 3-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.
PubMed | Institute Paoli Calmettes, Center Hospitalier, Departement de Genetique, University of Sousse and 7 more.
Type: Journal Article | Journal: Annals of hematology | Year: 2016
Familial aggregation of hematological malignancies has been reported highlighting inherited genetic predisposition. In this study, we targeted four candidate genes: JAK2 and RUNX1 genes assuring a prominent function in hematological process and CBL and NPM1 as proto-oncogenes. Their disruption was described in several sporadic hematological malignancies. The aim of this study is to determine whether JAK2, CBL, RUNX1, and NPM1 germline genes mutations are involved in familial hematological malignancies. Using direct sequencing, we analyzed JAK2 (exons 12 and 14); CBL (exons 7, 8 and 9); NPM1 (exon 12) and the entire RUNX1 in 88 independent families belonging to Tunisian and French populations. Twenty-one sporadic acute leukemias were included in this study. We reported a heterozygous intronic c.1641+6T>C JAK2 variant (rs182123615) found in two independent familial cases diagnosed with gastric lymphoma and Hodgkin lymphoma. The in silico analysis suggested a potential impact on splicing, but the functional splicing minigene reporter assay on rs182123615 variant showed no aberrant transcripts. In one sporadic acute myeloblastic leukemia, we reported an insertion 846 in. TGTT in exon 12 of NPM1 gene that may impact the normal reading frame. The rs182123615 JAK2 variant was described in several contexts including myeloproliferative neoplasms and congenital erythrocytosis and was supposed to be pathogenic. Through this current study, we established the assessment of pathogenicity of rs182123615 and we classified it rather as rare polymorphism.
PubMed | Hospital Universitario Clementino Fraga Filho, Nantes University Hospital Center, University of Strasbourg, Detska Fakultna Nemocnica and 31 more.
Type: Journal Article | Journal: Lancet (London, England) | Year: 2016
Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis.We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedmans test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960.Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study.Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate.Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).
PubMed | Institute Paoli Calmettes, Center Hospitalier, Departement de Genetique, University of Sousse and 6 more.
Type: Journal Article | Journal: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico | Year: 2016
Familial aggregation among patients with several hematological malignancies has been revealed. This emphasizes the importance of genetic factors. Only few genes predisposing to familial hematological malignancies have been reported until now due to the low occurrence. We have described in previous study PRF1 and CEBPA variants that might contribute to the background of genetic factors, which encourage us to extend our investigations to other cooperating genes. The aim of this study is to determine whether germline additional sex combs-like 1 (ASXL1) gene mutations may be involved?In this study, we investigated the candidate gene ASXL1 by direct sequencing in 88 unrelated Tunisian and French families with aggregated hematological malignancies.We report a new p.Arg402Gln germline missense substitution in two related Tunisian patients which has not been previously described. We identified here this variant for the first time in non-Hodgkin lymphoma. The p.Arg402Gln variant was not found in 200 control chromosomes. In silico analysis has predicted potential deleterious effect on ASXL1 protein.From an extended candidate genes analyzed in the field of familial hematological malignancies, ASXL1 might be involved. This variant should be considered since a potential damaging effect was predicted by in silico analysis, with a view to develop functional assay in order to investigate the biological assessment.
PubMed | Institute Paoli Calmettes, University of Sousse, Departement de Genetique, French Institute of Health and Medical Research and 8 more.
Type: Journal Article | Journal: Annals of hematology | Year: 2016
Isocitrate dehydrogenase IDH 1 and IDH 2 mutations were reported in several cancer forms, especially in hematological malignancies, but were never been investigated in familial aggregation. The aim of this study is to determine whether germline isocitrate dehydrogenase genes mutations are involved.We targeted IDH1 and IDH2 genes in 104 familial cases belonging to Tunisian and French populations, including several forms of hematological malignancies and cosegregated solid tumors.We report one IDH1 variant: c.315 G>T, p.Gly105Gly in 15% of cases, which was assigned to the worst outcome in several studies. Three IDH2 variants were found, among them, one intronic substitution c.543+45 G>A (rs142033117) and two new variants not previously described: c.389 A>T, p.Lys130Met and c.414 T>C, p.Thr138Thr. The p.Lys130Met was found in one case diagnosed with Waldenstroms disease with familial history of cancer. The enrolled in silico analysis, the functional study, and the absence of this variant in control population strengthen the hypothesis of its deleterious effect.From an extended number of candidate genes analyzed in familial hematological malignancies, IDH2 might be considerably involved since we reported a potential damaging effect.
PubMed | Institute Preparatoire aux Etudes Scientifiques et Techniques, INNTA National Institute of Nutrition and Food Technology, Montpellier SupAgro and Hopital dEnfants
Type: Journal Article | Journal: Nutrients | Year: 2016
In the framework of a worldwide policy to eliminate iodine deficiency (ID) disorders, universal salt iodization was adopted in Tunisia two decades ago. The present study aims to evaluate this strategy, using both performance and impact indicators. A total of 1560 children, aged 6-12 years, were randomly sampled using a national, two-stage, stratified, cross-sectional cluster survey in 2012. Urinary iodine concentration (UIC) of the subjects, and household salt iodine content, were analyzed. The national median UIC was 220 g/L (95% confidence interval (CI): 199-241), indicating an acceptable iodine status at the population level. Only 11.4% (95% CI: 8.6-14.9) of the children had UIC <100 g/L, but with large regional disparities (4.3% to 25.5%,
Mrani Alaoui N.,Pedagogical and Pediatrics Surgical Research Unit |
Lamalmi N.,Hopital dEnfants |
Saouab R.,Hopital dEnfants |
Gourinda H.,Pedagogical and Pediatrics Surgical Research Unit |
Dendane M.A.,Pedagogical and Pediatrics Surgical Research Unit
Annals of Vascular Surgery | Year: 2014
Synovial hemangioma is a rare benign vascular malformation. We report a case of chronic swelling in the left knee of a 7-year-old boy. An intra-articular tumor of synovial origin could was detected after a magnetic resonance imaging scan. Surgical excision of the mass associated with partial synovectomy was carried out. A histologic examination confirmed the diagnosis of synovial hemangioma. After 36 months of follow-up, there was no sign of recurrence. We review the literature and discuss the current case, along with noting the diagnostic methods and the therapeutic aspects of this rare and benign lesion. © 2014 by Elsevier Inc. All rights reserved.