RESUMO
UNLABELLED: Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reportedGATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome. KEY POINTS: Mutations of key transcription factor in myeloid malignancies.
Assuntos
Fator de Transcrição GATA2/genética , Doenças Genéticas Inatas/genética , Leucemia Mieloide Aguda/genética , Mutação de Sentido Incorreto , Síndromes Mielodisplásicas/genética , Neutropenia/genética , Adolescente , Adulto , Substituição de Aminoácidos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Criança , Pré-Escolar , Feminino , França , Fator de Transcrição GATA2/metabolismo , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/terapia , Loci Gênicos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Neutropenia/metabolismo , Linhagem , Sistema de RegistrosRESUMO
Mutations in DNMT3A encoding DNA methyltransferase 3A were recently described in patients with acute myeloid leukemia. To assess their prognostic significance, we determined the mutational status of DNMT3A exon 23 in 288 patients with AML excluding acute promyelocytic leukemia, aged from 18 to 65 years and treated in Toulouse University Hospital. A mutation was detected in 39 patients (13.5%). All DNMT3A exon 23+ patients had intermediate-risk cytogenetics. Mutations significantly correlated with a higher WBC count (p less than 0.001), NPM1 and FLT3-ITD mutations (p=0.027). DNMT3A mutations were conserved through xenotransplantation in immunodeficient mice. No difference in outcome between DNMT3A exon 23+ and DNMT3A exon 23- patients was found even if the results were stratified by NPM1 or FLT3-ITD status. However, DNMT3A exon 23+ patients had better median DFS (not reached vs 11.6 months, p=0.009) and OS (not reached vs 14.3 months, p=0.005) as compared to DNMT3A exon 23- patients when treated with idarubicin, whereas patients treated with daunorubicin had similar outcome regardless the DNMT3A status. This study shows that DNMT3A mutations have no impact on outcome but could be a predictive factor for response to idarubicin and thus, could have a direct influence in the way AML patients should be managed.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , DNA (Citosina-5-)-Metiltransferases/genética , Daunorrubicina/uso terapêutico , Idarubicina/uso terapêutico , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Idoso , Animais , DNA Metiltransferase 3A , Análise Mutacional de DNA , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Éxons , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Nucleofosmina , Prognóstico , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
INTRODUCTION: Von Hippel-Lindau (VHL) disease is an inherited syndrome caused by germline mutation in the VHL tumor suppressor gene predisposing to pancreatic endocrine tumors (PET). Whether these tumors derive from preexisting endocrine microadenomatosis as in multiple endocrine neoplasia type 1 (MEN1) is yet unknown. pVHL regulates hypoxia-inducible factor (HIF) that causes transcription activity of target genes like carbonic anhydrase 9 (CA9), vascular endothelial growth factor (VEGF), and cyclin D1. Our aim was to look for overexpression of these molecules to identify precursor endocrine lesions in the pancreas of VHL patients. METHODS: Nontumoral pancreas of 18 VHL patients operated on for PET, was examined for microadenomatosis (
Assuntos
Adenoma/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/análise , Biomarcadores Tumorais/análise , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Pâncreas/química , Neoplasias Pancreáticas/química , Lesões Pré-Cancerosas/química , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/metabolismo , Adenoma/genética , Adenoma/cirurgia , Adulto , Antígenos CD34/análise , Antígenos de Neoplasias/análise , Anidrase Carbônica IX , Anidrases Carbônicas/análise , Cromogranina A/análise , Ciclina D1/análise , Feminino , Glucagon/análise , Humanos , Imuno-Histoquímica , Insulina/análise , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/química , Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/cirurgia , Fator A de Crescimento do Endotélio Vascular/análise , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/cirurgiaRESUMO
Neoplasms with perivascular épithelioid-cell differentiation (PEComas) are rare tumors with a distinctive immunoreactivity for melanocytic markers. They have been described in various organs. We report an intrapancreatic PEComa discovered in a 46-year-old woman during a workup for diarrhea. CT scan showed a 1.7cm nodule in the body of the pancreas with slight-contrast enhancement at arterial time and isodense at portal time. The aspect was suggestive of an endocrine tumor despite negative somatostatin-receptor scintigraphy. Enucleation was performed. Pathologic evaluation showed a well-circumscribed intrapancreatic tumor consisting of a population of clear to eosinophilic spindle cells and a less abundant population of epithelioid cells arranged around blood vessels. Tumor cells expressed vimentin, HMB45 and actin and only focally S-100 protein, KL1, CD117 and CD34. These features were consistent with a PEComa. Pancreatic PEComas are rare, but should be included in the differential diagnostic of pancreatic clear cells tumors or pancreatic spindle- and epithelioid-cells tumors.