RESUMO
Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational "hot-spot" but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations.
Assuntos
Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/fisiologia , Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Mutação , Adolescente , Idade de Início , Sequência de Bases , Técnicas de Cultura de Células , Células Cultivadas , Criança , Pré-Escolar , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/epidemiologia , Proteína do Grupo de Complementação A da Anemia de Fanconi/metabolismo , Frequência do Gene , Humanos , Lactente , Modelos Biológicos , Dados de Sequência Molecular , Mutação/fisiologia , Fenótipo , Espanha/epidemiologiaRESUMO
BACKGROUND: Fanconi anaemia (FA) is a rare syndrome characterized by bone marrow failure, malformations and cancer predisposition. Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents such as diepoxybutane (DEB) or mitomycin C (MMC) is the 'gold standard' test for the diagnosis of FA. OBJECTIVE: To study the variability, the diagnostic implications and the clinical impact of chromosome fragility in FA. METHODS: Data are presented from 198 DEB-induced chromosome fragility tests in patients with and without FA where information on genetic subtype, cell sensitivity to MMC and clinical data were available. RESULTS: This large series allowed quantification of the variability and the level of overlap in ICL sensitivity among patients with FA and the normal population. A new chromosome fragility index is proposed that provides a cut-off diagnostic level to unambiguously distinguish patients with FA, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analysed, indicating that although both variables are correlated, 54% of patients with FA do not have spontaneous fragility. The data reveal a correlation between malformations and sensitivity to ICL-inducing agents. This correlation was also statistically significant when the analysis was restricted to patients from the FA-A complementation group. Finally, chromosome fragility does not correlate with the age of onset of haematological disease. CONCLUSIONS: This study proposes a new chromosome fragility index and suggests that genome instability during embryo development may be related to malformations in FA, while DEB-induced chromosome breaks in T cells have no prognostic value for the haematological disease.
Assuntos
Fragilidade Cromossômica , Anemia de Fanconi/genética , Reagentes de Ligações Cruzadas/farmacologia , Compostos de Epóxi/farmacologia , Anemia de Fanconi/diagnóstico , Humanos , Mitomicina/farmacologia , Mosaicismo , FenótipoRESUMO
INTRODUCTION: Outcomes in patients diagnosed of acute lymphoblastic leukemia with Philadelphia chromosome (Ph-ALL) remains unfavourable compared to other subtypes of acute lymphoblastic leukemia despite improvements in drug treatments as well as advances in hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: The role of allogeneic HSCT in Ph-ALL patients has been analysed through a multicentric study where data belonging to 70 patients diagnosed of this entity in different centers that received HSCT between years 1998 and 2014, were reported by the Grupo Español de Trasplante Hematopoyético (GETH). RESULTS: The performance of HSCT from year 2004, in first complete remission (CR) status with thymoglobulin (ATG) based conditioning had a favorable impact on overall survival (OS). HSTC performance from year 2004, in first CR with ATG-based conditioning in addition to acute graft versus host disease (aGvHD) development, increased event free survival (EFS). Treatment with imatinib as well as undetectable minimal residual disease (MRD) prior to HSCT, combined with aGvHD, reduced risk of relapse (RR). Patient age less than 10 years when HSCT, first CR and ATG-based conditioning were associated to a lower transplant related mortality (TRM). CONCLUSIONS: Patients that could achieve first CR that also received ATG-based conditioning had a better OS and EFS, so HSCT should be considered for this group of patients.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Criança , Humanos , Mesilato de Imatinib/uso terapêutico , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMO
INTRODUCTION: Outcomes in patients diagnosed of acute lymphoblastic leukemia with Philadelphia chromosome (Ph-ALL) remains unfavourable compared to other subtypes of acute lymphoblastic leukemia despite improvements in drug treatments as well as advances in hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: The role of allogeneic HSCT in Ph-ALL patients has been analysed through a multicentric study where data belonging to 70 patients diagnosed of this entity in different center that received HSCT between years 1998 and 2014, were reported by the Grupo Español de Trasplante Hematopoyético (GETH). RESULTS: The performance of HSCT from year 2004, in first complete remission (CR) status with thymoglobulin (ATG) based conditioning had a favorable impact on overall survival (OS). HSTC performance from year 2004, in first CR with ATG-based conditioning in addition to acute graft versus host disease (aGvHD) development, increased event free survival (EFS). Treatment with imatinib as well as undetectable minimal residual disease (MRD) prior to HSCT, combined with aGvHD, reduced risk of relapse (RR). Patient age less than 10 years when HSCT, first CR and ATG-based conditioning were associated to a lower transplant related mortality (TRM). CONCLUSIONS: Patients that could achieve first CR that also received ATG-based conditioning had a better OS and EFS, so HSCT should be considered for this group of patients.
RESUMO
BACKGROUND AND OBJECTIVES: A recently occurring increase of the prevalence of haemoglobinopathies, ß-thalassaemia major (TM) and sickle cell disease (SCD) over the last two decades in our country has generated new needs in terms of medical resources for both prevention and treatment of these patients. Allogeneic haematopoietic stem cell transplant (allo-HSCT) is a curative treatment available for patients who have severe haemoglobinopathies. The main objective of this study was to evaluate the results of allo-HSCT in paediatric patients with TM or SCD performed in paediatric hematopoietic transplant units within the Spanish Group of Bone Marrow Transplantation in Children (GETMON). MATERIAL AND METHODS: Retrospective review of patients undergoing HSCT in the GETMON units until 2015. RESULTS: A total of 65 patients were analysed (43 patients were affected with TM and 22 with SCD), who received allo-HSCT in 6 GETMON units between November 1989 and December 2014. Event-free survival three years post-transplant was 81% and overall survival 92% in patients with TM. Event-free survival three years post-transplant was 79% and overall survival 85% in patients with SCD. CONCLUSIONS: The results of this series are comparable to the results of other international series and offer a platform from which to continue trying to improve the evolution of these patients.
Assuntos
Anemia Falciforme/terapia , Transplante de Células-Tronco Hematopoéticas , Talassemia beta/terapia , Aloenxertos , Anemia Falciforme/mortalidade , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Intervalo Livre de Progressão , Estudos Retrospectivos , Espanha , Resultado do Tratamento , Talassemia beta/mortalidadeRESUMO
BACKGROUND: Fanconi anaemia is a heterogeneous genetic disease, where 12 complementation groups have been already described. Identifying the complementation group in patients with Fanconi anaemia constitutes a direct procedure to confirm the diagnosis of the disease and is required for the recruitment of these patients in gene therapy trials. OBJECTIVE: To determine the subtype of Fanconi anaemia patients in Spain, a Mediterranean country with a relatively high population (23%) of Fanconi anaemia patients belonging to the gypsy race. METHODS: Most patients could be subtyped by retroviral complementation approaches in peripheral blood T cells, although some mosaic patients were subtyped in cultured skin fibroblasts. Other approaches, mainly based on western blot analysis and generation of nuclear RAD51 and FANCJ foci, were required for the subtyping of a minor number of patients. RESULTS AND CONCLUSIONS: From a total of 125 patients included in the Registry of Fanconi Anaemia, samples from 102 patients were available for subtyping analyses. In 89 cases the subtype could be determined and in 8 cases exclusions of common complementation groups were made. Compared with other international studies, a skewed distribution of complementation groups was observed in Spain, where 80% of the families belonged to the Fanconi anaemia group A (FA-A) complementation group. The high proportion of gypsy patients, all of them FA-A, and the absence of patients with FA-C account for this characteristic distribution of complementation groups.
Assuntos
Algoritmos , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Anemia de Fanconi/classificação , Heterogeneidade Genética , Roma (Grupo Étnico)/genética , Células Cultivadas/química , Células Cultivadas/efeitos dos fármacos , Consanguinidade , Resistência a Medicamentos/genética , Compostos de Epóxi/farmacologia , Anemia de Fanconi/epidemiologia , Anemia de Fanconi/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/análise , Proteínas de Grupos de Complementação da Anemia de Fanconi/deficiência , Fibroblastos/química , Fibroblastos/patologia , Teste de Complementação Genética , Genótipo , Humanos , Incidência , Mitomicina/farmacologia , Mosaicismo , Sistema de Registros , Retroviridae/genética , Espanha/epidemiologia , Linfócitos T/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia , Transdução GenéticaRESUMO
Introducción: Los resultados de los pacientes con diagnóstico de leucemia linfoblástica aguda con cromosoma de Philadelphia (LLA-Ph) continúan siendo desfavorables comparados con los otros tipos de leucemias linfoblásticas agudas, pese a las mejoras en los tratamientos farmacológicos y los avances del trasplante de progenitores hematopoyéticos (TPH).Pacientes y métodos: Se ha analizado el papel del TPH alogénico en pacientes diagnosticados de LLA-Ph mediante un estudio multicéntrico donde se recogen datos pertenecientes a 70 pacientes reportados por el Grupo Español de Trasplante Hematopoyético (GETH), diagnosticados de esta enfermedad trasplantados en distintos hospitales españoles entre los años 1998 y 2014.Resultados: La realización del TPH a partir del año 2004, en primera remisión completa (RC) y con el empleo de timoglobulina (ATG) como parte del acondicionamiento, impactó favorablemente en la supervivencia global (SG). El TPH a partir del año 2004 en primera RC, así como el tratamiento con ATG y el desarrollo de enfermedad de injerto contra receptor aguda (EICRa), aumentaron la supervivencia libre de eventos (SLE). La administración de imatinib, así como la ausencia de enfermedad mínima residual previas al TPH, junto con la EICRa redujeron la probabilidad de recaída. La edad del paciente inferior a 10 años, el estado de primera RC y el empleo de ATG en el acondicionamiento disminuyeron la mortalidad relacionada con el TPH.Conclusiones: Los pacientes en primera RC que han recibido ATG durante el acondicionamiento presentan mayores SG y SLE. La indicación de TPH debería considerarse en estas situaciones. (AU)
Introduction: Outcomes in patients diagnosed of acute lymphoblastic leukemia with Philadelphia chromosome (Ph-ALL) remains unfavourable compared to other subtypes of acute lymphoblastic leukemia despite improvements in drug treatments as well as advances in hematopoietic stem cell transplantation (HSCT).Patients and methods: The role of allogeneic HSCT in Ph-ALL patients has been analysed through a multicentric study where data belonging to 70 patients diagnosed of this entity in different center that received HSCT between years 1998 and 2014, were reported by the Grupo Español de Trasplante Hematopoyético (GETH).Results: The performance of HSCT from year 2004, in first complete remission (CR) status with thymoglobulin (ATG) based conditioning had a favorable impact on overall survival (OS). HSTC performance from year 2004, in first CR with ATG-based conditioning in addition to acute graft versus host disease (aGvHD) development, increased event free survival (EFS). Treatment with imatinib as well as undetectable minimal residual disease (MRD) prior to HSCT, combined with aGvHD, reduced risk of relapse (RR). Patient age less than 10 years when HSCT, first CR and ATG-based conditioning were associated to a lower transplant related mortality (TRM).Conclusions: Patients that could achieve first CR that also received ATG-based conditioning had a better OS and EFS, so HSCT should be considered for this group of patients. (AU)
Assuntos
Humanos , Criança , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , 28599 , Mortalidade InfantilRESUMO
Antecedentes y objetivos: El incremento descrito en la prevalencia de hemoglobinopatías, de ß-talasemia mayor (TM) y de enfermedad drepanocítica (ED) que ha ocurrido en las últimas dos décadas en nuestro país ha generado nuevas necesidades en cuanto a recursos médicos tanto para la prevención como para el tratamiento de estos pacientes. El trasplante alogénico de progenitores hematopoyéticos (alo-TPH) es el tratamiento curativo disponible en nuestro medio para pacientes con hemoglobinopatías graves. El objetivo principal de este estudio fue conocer los resultados del alo-TPH en pacientes pediátricos con TM o ED realizados en unidades de trasplante hematopoyético pediátrico incluidas dentro del Grupo Español de Trasplante de Médula Ósea en Niños (GETMON). Material y métodos: Revisión retrospectiva de los pacientes sometidos a TPH en unidades de TPH del GETMON hasta el año 2015. Resultados: Se analizaron un total de 65 pacientes (43 pacientes afectados de TM y 22 de ED) que recibieron el alo-TPH en 6 unidades GETMON entre noviembre de 1989 y diciembre de 2014. La supervivencia libre de eventos 3años postrasplante fue del 81% y la supervivencia global del 92% en pacientes con TM. La supervivencia libre de eventos 3años postrasplante fue del 79% y la supervivencia global del 85% en pacientes con ED. Conclusiones: Los resultados de esta serie son comparables a los resultados de otras series internacionales y ofrecen un punto de partida para continuar intentando mejorar la evolución de estos pacientes
Background and objectives: A recently occurring increase of the prevalence of haemoglobinopathies, ß-thalassaemia major (TM) and sickle cell disease (SCD) over the last two decades in our country has generated new needs in terms of medical resources for both prevention and treatment of these patients. Allogeneic haematopoietic stem cell transplant (allo-HSCT) is a curative treatment available for patients who have severe haemoglobinopathies. The main objective of this study was to evaluate the results of allo-HSCT in paediatric patients with TM or SCD performed in paediatric hematopoietic transplant units within the Spanish Group of Bone Marrow Transplantation in Children (GETMON). Material and methods: Retrospective review of patients undergoing HSCT in the GETMON units until 2015. Results: A total of 65 patients were analysed (43 patients were affected with TM and 22 with SCD), who received allo-HSCT in 6 GETMON units between November 1989 and December 2014. Event-free survival three years post-transplant was 81% and overall survival 92% in patients with TM. Event-free survival three years post-transplant was 79% and overall survival 85% in patients with SCD. Conclusions: The results of this series are comparable to the results of other international series and offer a platform from which to continue trying to improve the evolution of these patients