RESUMEN
While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown. Using single cell RNA-seq (scRNA-seq) on CD34+ progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Interestingly, both del(5q) and non-del(5q) cells present similar transcriptional lesions, indicating that all cells, and not only those harboring the deletion, may contribute to aberrant hematopoietic differentiation. However, gene regulatory network (GRN) analyses reveal a group of regulons showing aberrant activity that could trigger altered hematopoiesis exclusively in del(5q) cells, pointing to a more prominent role of these cells in disease phenotype. In del(5q) MDS patients achieving hematological response upon lenalidomide treatment, the drug reverts several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remain, which may be responsible for potential future relapses. Moreover, lack of hematological response is associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study reveals transcriptional alterations that could contribute to the pathogenesis and treatment response of del(5q) MDS.
Asunto(s)
Antígenos CD34 , Deleción Cromosómica , Cromosomas Humanos Par 5 , Células Madre Hematopoyéticas , Lenalidomida , Síndromes Mielodisplásicos , Análisis de la Célula Individual , Humanos , Lenalidomida/farmacología , Lenalidomida/uso terapéutico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/metabolismo , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Antígenos CD34/metabolismo , Cromosomas Humanos Par 5/genética , Masculino , Femenino , Anciano , Redes Reguladoras de Genes/efectos de los fármacos , Persona de Mediana Edad , Hematopoyesis/efectos de los fármacos , Hematopoyesis/genética , Transcriptoma , Anciano de 80 o más Años , RNA-Seq , Perfilación de la Expresión GénicaRESUMEN
We hypothesized that the dynamic acquisition of cytogenetic abnormalities (ACA) during the follow up of myelodysplastic syndromes (MDS) could be associated with poor prognosis. We conducted a retrospective analysis of 365 patients with IPSS low or intermediate-1 risk MDS who had at least two consecutive cytogenetic analyses during the follow up. Acquisition of cytogenetic abnormalities was detected in 107 patients (29%). The most frequent alteration involved chromosome 7 in 21% of ACA cases. Median transformation-free and overall survival for patients with and without ACA were 13 vs. 52 months (P = 0.01) and 17 vs. 62 months (P = 0.01), respectively. By fitting ACA as a time-dependent covariate, multivariate Cox regression analysis showed that patients with ACA had increased risk of transformation (HR = 1.40; P = 0.03) or death (HR = 1.45; P = 0.02). Notably, female patients with therapy-related MDS (t-MDS) had an increased risk of developing ACA (OR = 5.26; P < 0.0001), although subgroup analysis showed that prognostic impact of ACA was not evident in t-MDS. In conclusion, ACA occurs in close to one third of patients with IPSS defined lower risk MDS, more common among patients with t-MDS, but has a significant prognostic impact on de novo MDS.
Asunto(s)
Transformación Celular Neoplásica/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 7/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/terapia , Pronóstico , Factores de Riesgo , Factores Sexuales , Tasa de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: Cyclin D1-negative mantle cell lymphoma is difficult to distinguish from other small B-cell lymphomas. The clinical and pathological characteristics of patients with this form of lymphoma have not been well defined. Overexpression of the transcription factor SOX11 has been observed in conventional mantle cell lymphoma. The aim of this study was to determine whether this gene is expressed in cyclin D1-negative mantle cell lymphoma and whether its detection may be useful to identify these tumors. DESIGN AND METHODS: The microarray database of 238 mature B-cell neoplasms was re-examined. SOX11 protein expression was investigated immunohistochemically in 12 cases of cyclin D1-negative mantle cell lymphoma, 54 cases of conventional mantle cell lymphoma, and 209 additional lymphoid neoplasms. RESULTS: SOX11 mRNA was highly expressed in conventional and cyclin D1-negative mantle cell lymphoma and in 33% of the cases of Burkitt's lymphoma but not in any other mature lymphoid neoplasm. SOX11 nuclear protein was detected in 50 cases (93%) of conventional mantle cell lymphoma and also in the 12 cyclin D1-negative cases of mantle cell lymphoma, the six cases of lymphoblastic lymphomas, in two of eight cases of Burkitt's lymphoma, and in two of three T-prolymphocytic leukemias but was negative in the remaining lymphoid neoplasms. Cyclin D2 and D3 mRNA levels were significantly higher in cyclin D1-negative mantle cell lymphoma than in conventional mantle cell lymphoma but the protein expression was not discriminative. The clinico-pathological features and outcomes of the patients with cyclin D1-negative mantle cell lymphoma identified by SOX11 expression were similar to those of patients with conventional mantle cell lymphoma. CONCLUSIONS: SOX11 mRNA and nuclear protein expression is a highly specific marker for both cyclin D1-positive and negative mantle cell lymphoma.
Asunto(s)
Ciclina D1/deficiencia , Linfoma de Células del Manto/patología , Factores de Transcripción SOXC/análisis , Adulto , Anciano , Biomarcadores de Tumor , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma/patología , Linfoma de Células del Manto/química , Linfoma de Células del Manto/terapia , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/genética , ARN Mensajero/análisis , Factores de Transcripción SOXC/genética , Resultado del TratamientoRESUMEN
BACKGROUND: Follicular lymphomas are currently subdivided into grades I, II, IIIa and IIIb. This distinction is, however, questioned. DESIGN AND METHODS: We studied the gene expression profile of 43 follicular lymphomas, 50 B-cell non-Hodgkin's lymphomas of different histotype, and 20 samples of normal B-lymphocytes in order to assess: (i) the relationship of follicular lymphoma with normal B cells and other B-cell non-Hodgkin's lymphomas; (ii) whether follicular lymphoma is a unique disease; and (iii) whether follicular lymphoma grade IIIb is closer to follicular lymphoma or diffuse large B-cell lymphoma of the germinal center B-cell type. RESULTS: First, we found that the molecular profile of follicular lymphoma is intimately related to that of normal germinal center B cells, irrespectively of the histological grade. Secondly, we observed that follicular lymphoma has a relatively homogeneous gene expression profile that is distinct from that of other B-cell non-Hodgkin's lymphoma and does not include discrete molecular subgroups. However, by further clustering samples according to signatures differentially expressed among follicular lymphomas or in follicular lymphomas versus diffuse large B-cell lymphoma, we showed that grade I-IIIa tumors tend to cluster together, while grade IIIb follicular lymphoma constitutes a distinct subgroup, whose molecular signature is closer to that of the remaining follicular lymphomas than to that of diffuse large B-cell lymphoma of the germinal center B-cell type. CONCLUSIONS: These data support the hypothesis that grade IIIb follicular lymphoma does indeed belong to the group of follicular lymphomas rather than diffuse large B-cell lymphomas, and also suggests a possible revision of the histological grading of follicular lymphomas, with their simple distinction into follicular lymphoma (grade I-IIIa) and follicular lymphoma/large cell (grade IIIb).
Asunto(s)
Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B/genética , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Linfoma no Hodgkin/genética , Adulto , Anciano , Análisis por Conglomerados , Femenino , Genoma Humano , Humanos , Linfoma de Células B/diagnóstico , Linfoma Folicular/clasificación , Linfoma no Hodgkin/diagnóstico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Circulating tumor cells (CTCs) are frequently associated with epithelial-mesenchymal transition (EMT).The objective of this study was to detect EMT phenotype through Vimentin (VIM) and Slug expression in cytokeratin (CK)-negative CTCs in non-metastatic breast cancer patients and to determine the importance of EGFR in the EMT phenomenon. In CK-negative CTCs samples, both VIM and Slug markers were co-expressed in the most of patients. Among patients EGFR+, half of them were positive for these EMT markers. Furthermore, after a systemic treatment 68% of patients switched from CK- to CK+ CTCs. In our experimental model we found that activation of EGFR signaling by its ligand on MCF-7 cells is sufficient to increase EMT phenotypes, to inhibit apoptotic events and to induce the loss of CK expression. The simultaneous detection of both EGFR and EMT markers in CTCs may improve prognostic or predictive information in patients with operable breast cancer.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Transición Epitelial-Mesenquimal/fisiología , Receptores ErbB/biosíntesis , Células Neoplásicas Circulantes/patología , Adulto , Anciano , Western Blotting , Neoplasias de la Mama/metabolismo , Receptores ErbB/análisis , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Queratinas/biosíntesis , Células MCF-7 , Microscopía Confocal , Persona de Mediana Edad , Células Neoplásicas Circulantes/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Transcripción de la Familia Snail , Factores de Transcripción/análisis , Factores de Transcripción/biosíntesis , Vimentina/análisis , Vimentina/biosíntesisRESUMEN
INTRODUCTION: Translocation of the anaplastic lymphoma kinase (ALK) gene is involved in the tumorigenesis of a subset of non-small cell lung carcinomas (NSCLCs) and identifies patients sensitive to ALK inhibitors. ALK copy number changes and amplification, which plays an oncogenic role in tumors such as neuroblastoma, are poorly characterized in NSCLC. We aimed to study the prevalence of ALK copy number changes and their correlation to ALK protein expression, epidermal growth factor receptor (EGFR) status, and clinicopathological data in patients with NSCLC. METHODS: ALK status was evaluated by fluorescence in situ hybridization (FISH). Specimens with ALK translocation were studied for echinoderm microtubule-associated protein-like 4 (EML4), KIF5B, and TFG status. ALK expression was assessed by immunohistochemistry. EGFR gene and protein status were evaluated in adenocarcinomas. Survival analysis was performed. RESULTS: One hundred seven NSCLC cases were evaluated. There were two cases of EML4-ALK translocation and one with an atypical translocation of ALK. Both cases of EML4-ALK translocation had ALK protein expression, whereas in the rest, ALK was undetected. Eleven cases (10%) exhibited ALK amplification and 68 (63%) copy number gains. There was an association between ALK amplification and EGFR FISH positivity (p < 0.0001) but not with prognosis. In conclusion, EML4-ALK translocation is a rare event in NSCLC. CONCLUSION: The study reveals a significant frequency of ALK amplification and its association with EGFR FISH positivity in lung adenocarcinomas. Based on these findings, a potential role of ALK amplification in the response to ALK inhibitors alone or combined with EGFR inhibitors in NSCLC merits further studies.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Amplificación de Genes , Dosificación de Gen , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinasas/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/patología , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , ADN de Neoplasias/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mutación/genética , Estadificación de Neoplasias , Proteínas de Fusión Oncogénica/genética , Reacción en Cadena de la Polimerasa , Pronóstico , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas Receptoras , Translocación GenéticaRESUMEN
Se realiza un breve esbozo de las diferentes causas de muerte de acuerdo con la clasificación NASH y se profundiza en la historia del suicidio con énfasis en los aspectos causales referidos por Freud, Durkheim y Menninger, se critican éstos por su enfoque unilateral y se acepta la génesis multifactorial de dicha conducta. Se analizan las diferentes clasificaciones según los métodos, la dinámica y los agentes, así como los llamados factores de riesgo que predisponen al suicidio. Se discute la participación del médico de la familia en el mejor cumplimiento del Programa Nacional de Prevención de la Conducta Suicida y se sugiere cómo valorar adecuadamente a un paciente con riesgo suicida (AU)
Asunto(s)
Humanos , Suicidio/clasificación , Suicidio/historia , Suicidio/prevención & control , Factores de Riesgo , Medicina Comunitaria , Medicina Familiar y ComunitariaRESUMEN
Fundamento. Éste es un caso poco frecuente de secuencia óculo-aurículo-vertebral, ya que fue diagnosticado precozmente, en la etapa neonatal inmediata, y por lo tanto se pudo estudiar ampliamente pronto, tanto en el aspecto genético como en cuanto a otras posibles malformaciones asociadas. Observación clínica. Recién nacido varón a término, de peso adecuado para la edad de gestación, que fue diagnosticado inmediatamente después de nacer de secuencia óculo-aurículo-vertebral al presentar 6 criterios clínicos: mamelones cartilaginosos preauriculares bilaterales, macrostomía, coloboma en el párpado superior derecho, Úpodermoide epibulbar derecho, defecto de la comisura palpebral derecha y foseta sacrocoxígea. Se investigó la presencia de malformaciones oculoauriculovertebrales en sus familiares sin encontrar ningún caso, pon lo que se orientó como un caso esporádico. Se realizó un estudio cromosómico del niño y sus padres, que resultó normal. Todas las exploraciones complementarias para detectar malformaciones asociadas fueron normales, excepto una deficiencia auditiva periférica de conducción. Discusión. Hay varias teorías sobre la etiología de la secuencia óculo-aurículo-vertebral y aunque se ha comprobado que la mayoría de los casos son esporádicos, se tienen evidencias claras sobre ciertos patrones familiares de herencia autosómica dominante, o incluso de herencia autosómica recesiva. Es importante pensar en esta secuencia siempre que se encuentre en un recién nacido la presencia de algunas de las malformaciones menores más frecuentes que componen esta compleja secuencia, como los apéndices preauriculares. (AU)