RESUMO
Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure disorder linked predominantly to ribosomal protein gene mutations. Here the European DBA consortium reports novel mutations identified in the RPL15 gene in 6 unrelated individuals diagnosed with DBA. Although point mutations have not been previously reported for RPL15, we identified 4 individuals with truncating mutations p.Tyr81* (in 3 of 4) and p.Gln29*, and 2 with missense variants p.Leu10Pro and p.Lys153Thr. Notably, 75% (3 of 4) of truncating mutation carriers manifested with severe hydrops fetalis and required intrauterine transfusions. Even more remarkable is the observation that the 3 carriers of p.Tyr81* mutation became treatment-independent between four and 16 months of life and maintained normal blood counts until their last follow up. Genetic reversion at the DNA level as a potential mechanism of remission was not observed in our patients. In vitro studies revealed that cells carrying RPL15 mutations have pre-rRNA processing defects, reduced 60S ribosomal subunit formation, and severe proliferation defects. Red cell culture assays of RPL15-mutated primary erythroblast cells also showed a severe reduction in cell proliferation, delayed erythroid differentiation, elevated TP53 activity, and increased apoptosis. This study identifies a novel subgroup of DBA with mutations in the RPL15 gene with an unexpected high rate of hydrops fetalis and spontaneous, long-lasting remission.
Assuntos
Anemia de Diamond-Blackfan/complicações , Anemia de Diamond-Blackfan/genética , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/etiologia , Mutação , Complicações Hematológicas na Gravidez , Proteínas Ribossômicas/genética , Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/terapia , Apoptose/genética , Biomarcadores , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células , Análise Mutacional de DNA , Índices de Eritrócitos , Feminino , Genes p53 , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Gravidez , Biossíntese de ProteínasRESUMO
Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Kraków, Poland The review of literature indicates that several clinico-morphological factors such as location of the primary tumour as well as its size, histologic subtype, and grade or even selected molecular changes may significantly affect survival of liposarcoma (LPS) patients. Data concerning prognostic importance of DNA ploidy status in LPS cells are extremely limited and results of flow cytometry (FCM) studies have never been compiled with the current classification of malignant adipocytic tumours. Based on evaluation of material from 54 liposarcomas which was available for both histological and FCM analysis, we distinguished four prognostic groups of patients. The best prognosis was noticed for diploid and grade G1 well-differentiated or myxoid liposarcomas localised on extremities. None of the patients with lipoma-like WDLPS and myxoid liposarcoma grade 1 metastasised, while metastases were observed among patients with dedifferentiated LPS (70% of 5-year MFS) and cellular myxoid or round cell liposarcoma (20% of 5-year MFS, only). The metastasis-free survival curves for the above mentioned groups of patients differed significantly (p = 0.00001).
Assuntos
Diferenciação Celular , Lipossarcoma Mixoide/genética , Lipossarcoma Mixoide/patologia , Lipossarcoma/genética , Lipossarcoma/patologia , Ploidias , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Lipossarcoma/mortalidade , Lipossarcoma/terapia , Lipossarcoma Mixoide/mortalidade , Lipossarcoma Mixoide/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
More than ten years ago we made first attempts at valuating a prognostic power of flow cytometric DNA measurement results for patients with non-Hodgkin's lymphoma. In multivariate overall survival analysis, S-phase fraction (SPF) showed to be the only independent prognostic factor within the group of patients with low grade lymphomas. In this paper, we have tried to check our previous results in a greater group of patients with longer follow-up, within the specific types of B-cell and T/NK-cell lymphomas verified and classified according to criteria of the WHO 2008 classification. The study was performed on the material obtained from biopsies (85% of lymph nodes) of 484 NHL patients. Patients were diagnosed from 1991 to 2007. The medium follow-up time for living patients was 69 months (range: 25-202 months). All specimens were verified histologically and immunohistochemically. Ploidy and SPF were determined by flow cytometry on fresh tissue obtained during the diagnostic procedure. The diagnostic importance of ploidy and SPF has been confirmed. Ploidy had no predictive or prognostic impact in any of the NHL types, whereas SPF was found to be an independent predictive or prognostic factor in B-CLL/SLL, DLBCL and ALCL.