RESUMEN
We describe a 12-year-old girl, simultaneously presenting with colonic adenocarcinoma and medulloblastoma from bialleic deletions in the mismatch repair gene PMS2. Her distinctive physical and clinical findings are characteristic of constitutional mismatch repair deficiency syndrome. Earlier recognition of such findings may permit better screening and more effective treatment.
Asunto(s)
Adenocarcinoma/genética , Adenosina Trifosfatasas/genética , Neoplasias Cerebelosas/genética , Neoplasias del Colon/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Eliminación de Gen , Meduloblastoma/genética , Neoplasias Primarias Múltiples/genética , Alelos , Niño , Femenino , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento IncorrectoRESUMEN
Classic Hodgkin lymphoma (CHL) patients may infrequently present with a prior or recurrent disease with discordant histology resembling non-Hodgkin lymphomas. These include primary mediastinal large B-cell lymphoma (PMBL), diffuse large B-cell lymphoma (DLBCL), or mediastinal gray-zone lymphoma (MGZL). Such patients are often refractory to standard therapy and their diagnosis is hampered by significant morphologic and immunophenotypic overlap and insufficient molecular data. Among 509 CHL patients seen at an academic medical center, 6 patients had a prior or subsequent diagnosis different from CHL. Paired tissue samples were evaluated by targeted mutational analysis using a 164-gene panel. Our findings show multiple shared variants indicative of a clonal relationship between the CHL and the PMBL, DLBCL, or MGZL diagnoses. Most frequent mutated genes included TNFAIP3 (4 of 6, 66.7%), STAT6 (3 or 6, 50%), ARID1A (3 of 6, 50%), and XPO1 (3 of 5, 60%). Three patients showed the same oncogenic variant within the XPO1 gene (E571K), and mutations in TNFAIP3 and B2M were observed in 2 of the 5 patients with shared variants. In addition, differences in the mutation profile between the lymphoma pairs were also observed, which could represent clonal evolution. Mutational profiling could be of benefit in patients with recurrent/refractory disease with discordant histology, where the clonal relationship could be helpful to inform and guide therapeutic decisions. These findings provide further evidence of a true biological continuum surrounding CHL, PMBL, DLBCL, and MGZL and shed light on underlying genetic events and their clinical impact.
Asunto(s)
Enfermedad de Hodgkin , Linfoma de Células B Grandes Difuso , Neoplasias del Mediastino , Humanos , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/terapia , Neoplasias del Mediastino/diagnóstico , Enfermedad de Hodgkin/diagnóstico , Linfoma de Células B Grandes Difuso/patología , Inmunofenotipificación , MutaciónRESUMEN
Ability to grow under anchorage-independent conditions is one of the major hallmarks of transformed cells. Key to this is the capacity of cells to suppress anoikis, or programmed cell death induced by detachment from the extracellular matrix. To model this phenomenon in vitro, we plated Ewing tumor cells under anchorage-independent conditions by transferring them to dishes coated with agar to prevent attachment to underlying plastic. This resulted in marked up-regulation of E-cadherin and rapid formation of multicellular spheroids in suspension. Addition of calcium chelators, antibodies to E-cadherin (but not to other cadherins or beta(1)-integrin), or expression of dominant negative E-cadherin led to massive apoptosis of spheroid cultures whereas adherent cultures were unaffected. This correlated with reduced activation of the phosphatidylinositol 3-kinase-Akt pathway but not the Ras-extracellular signal-regulated kinase 1/2 cascade. Furthermore, spheroid cultures showed profound chemoresistance to multiple cytotoxic agents compared with adherent cultures, which could be reversed by alpha-E-cadherin antibodies or dominant negative E-cadherin. In a screen for potential downstream effectors of spheroid cell survival, we detected E-cadherin-dependent activation of the ErbB4 receptor tyrosine kinase but not of other ErbB family members. Reduction of ErbB4 levels by RNA interference blocked Akt activation and spheroid cell survival and restored chemosensitivity to Ewing sarcoma spheroids. Our results indicate that anchorage-independent Ewing sarcoma cells suppress anoikis through a pathway involving E-cadherin cell-cell adhesion, which leads to ErbB4 activation of the phosphatidylinositol 3-kinase-Akt pathway, and that this is associated with increased resistance of cells to cytotoxic agents.
Asunto(s)
Anoicis/fisiología , Neoplasias Óseas/patología , Cadherinas/metabolismo , Receptores ErbB/metabolismo , Sarcoma de Ewing/patología , Neoplasias Óseas/enzimología , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Cadherinas/biosíntesis , Cadherinas/genética , Adhesión Celular/fisiología , Comunicación Celular/fisiología , Línea Celular Tumoral , Activación Enzimática , Receptores ErbB/biosíntesis , Receptores ErbB/genética , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-4 , Sarcoma de Ewing/enzimología , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Transducción de Señal , Esferoides Celulares , Regulación hacia ArribaRESUMEN
Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes to multiple malignancies, most commonly colorectal carcinoma, but has rarely been associated with lymphoma. We discuss one patient found to have Burkitt-like Lymphoma (BLL) with 11q aberration in the setting of previously undiagnosed FAP. We review the literature of FAP and associated malignancies and the provisional WHO classification of Burkitt-like lymphoma with 11q aberration. Both FAP and Burkitt-like lymphoma with 11q aberration involve perturbation of the MYC network and this may provide insight into a connection between these two diagnoses. However, further study is needed to elucidate if there is an increased risk of BLL and other subtypes of lymphoma among patients with FAP in order to provide optimal counseling and surveillance for patients with FAP.
Asunto(s)
Poliposis Adenomatosa del Colon , Linfoma de Burkitt , Abdomen/diagnóstico por imagen , Abdomen/patología , Poliposis Adenomatosa del Colon/complicaciones , Poliposis Adenomatosa del Colon/diagnóstico , Poliposis Adenomatosa del Colon/genética , Adolescente , Linfoma de Burkitt/complicaciones , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/genética , Aberraciones Cromosómicas , Humanos , MasculinoRESUMEN
With the increasing amount of violence prevalent in our society, it is inevitable that this violence will enter emergency departments. Nurses are increasingly likely to see guns and other deadly weapons in the emergency department. The purpose of this article is to explain how a firearm works and how to safely handle and store the weapon until someone with more training can take possession of the weapon.
Asunto(s)
Servicio de Urgencia en Hospital/organización & administración , Armas de Fuego , Salud Laboral , Administración de la Seguridad/organización & administración , Medidas de Seguridad/organización & administración , Violencia/prevención & control , Diseño de Equipo , Seguridad de Equipos , Armas de Fuego/clasificación , Humanos , Personal de Enfermería en Hospital/organización & administración , Personal de Enfermería en Hospital/psicologíaRESUMEN
Nearly all cases of Ewing Family Tumors (EFT) harbor chimeric EWS/ETS transcription factors which are thought to aberrantly regulate transcriptional targets of phenotypic consequence. We have recently demonstrated that EWS/ETS proteins up-regulate platelet derived growth factor-C (PDGF-C), a novel transforming growth factor. To determine if PDGF-C signaling contributes to the malignant phenotype of EFT cell lines, we attempted to disrupt this presumed autocrine loop. AG1296, a PDGF receptor selective tyrosine kinase inhibitor, markedly inhibits anchorage-independent growth in an EFT cell line. To effect specific disruption, we have developed a dominant negative form of PDGF-C which is appropriately secreted and processed. This mutant has greatly reduced activity as a PDGF receptor agonist. When co-expressed with PDGF-C in a fibroblast transformation model, this dominant negative dramatically inhibits anchorage-independent growth. When this mutant is expressed in EFT cell lines, there is a similar reduction in anchorage-independent growth. This demonstrates that specific inhibition of PDGF-C signaling in EFT cell lines partially reverts their phenotype. These data support a significant role of PDGF-C in the biology of EFT. They also suggest that PDGF-C driven signaling may be a possible therapeutic target of more clinically relevant tyrosine kinase inhibitors.
Asunto(s)
Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Crecimiento Derivado de Plaquetas/fisiología , Sarcoma de Ewing/metabolismo , Células 3T3 , Animales , Western Blotting , División Celular , Línea Celular , Dimerización , Inhibidores Enzimáticos/farmacología , Genes Dominantes , Proteínas Fluorescentes Verdes , Humanos , Proteínas Luminiscentes/metabolismo , Linfocinas , Ratones , Fenotipo , Pruebas de Precipitina , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal , Transfección , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
Ewing Family Tumors (Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor) are common bone and soft tissue malignancies of childhood, adolescence and young adulthood. Chromosomal translocation in these tumors produces fusion oncogenes of the EWS/ETS class, with EWS/FLI1 being by far the most common. EWS/ETS chimera are the only well established driver mutations in these tumors and they function as aberrant transcription factors. Understanding the downstream genes whose expression is modified has been a central approach to the study of these tumors. FOXM1 is a proliferation associated transcription factor which has increasingly been found to play a role in the pathogenesis of a wide range of human cancers. Here we demonstrate that FOXM1 is expressed in Ewing primary tumors and cell lines. Reduction in FOXM1 expression in Ewing cell lines results in diminished potential for anchorage independent growth. FOXM1 expression is enhanced by EWS/FLI1, though, unlike other tumor systems, it is not driven by expression of the EWS/FLI1 target GLI1. Thiostrepton is a compound known to inhibit FOXM1 by direct binding. We show that Thiostrepton diminishes FOXM1 expression in Ewing cell lines and this reduction reduces cell viability through an apoptotic mechanism. FOXM1 is involved in Ewing tumor pathogenesis and may prove to be a useful therapeutic target in Ewing tumors.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Fusión Oncogénica/genética , Proteína Proto-Oncogénica c-fli-1/genética , Proteína EWS de Unión a ARN/genética , Sarcoma de Ewing/genética , Adolescente , Animales , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Biopsia , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Adhesión Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Niño , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/antagonistas & inhibidores , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Células 3T3 NIH , Proteínas de Fusión Oncogénica/metabolismo , Proteína Proto-Oncogénica c-fli-1/metabolismo , ARN Interferente Pequeño/genética , Proteína EWS de Unión a ARN/metabolismo , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patología , Transducción de Señal/efectos de los fármacos , Tioestreptona/farmacología , Translocación Genética , Adulto JovenRESUMEN
Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352). The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR) analysis), p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC) or the lower tested concentration (LTC): (cyclophosphamide (as 4-HC) and doxorubicin at CAC, etoposide, irinotecan (as SN-38) and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.
Asunto(s)
Antineoplásicos/farmacología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Sarcoma de Ewing/metabolismo , Proteína p14ARF Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Resistencia a Antineoplásicos/genética , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Proteína p14ARF Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The Ewing Sarcoma Family Tumors (ESFT) consist of the classical pathologic entities of Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor. Occurring largely in the childhood through young adult years, these tumors have an unsurpassed propensity for metastasis and have no defined cell of origin. The biology of these aggressive malignancies centers around EWS/FLI1 and related EWS/ETS chimeric transcription factors, which are largely limited to this tumor class. Much progress has been made in the identification of a network of loci whose expression is modulated by EWS/FLI1 and its congeners. To date, little progress has been made in reconstructing the sequence of direct and indirect events that produce this network of modulated loci. The recent identification of GLI1 as an upregulated target of EWS/ETS transcription factors suggests a target which may be a more central mediator in the ESFT signaling network. In this paper, we further define the relationship of EWS/FLI1 expression and GLI1 upregulation in ESFT. This relationship is supported with data from primary tumor specimens. It is consistently observed across multiple ESFT cell lines and with multiple means of EWS/FLI1 inhibition. GLI1 inhibition affects tumor cell line phenotype whether shRNA or endogenous or pharmacologic inhibitors are employed. As is seen in model transformation systems, GLI1 upregulation by EWS/FLI1 appears to be independent of Hedgehog stimulation. Consistent with a more central role in ESFT pathogenesis, several known EWS/FLI1 targets appear to be targeted through GLI1. These findings further establish a central role for GLI1 in the pathogenesis of Ewing Tumors.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Proteínas de Fusión Oncogénica/metabolismo , Proteína Proto-Oncogénica c-fli-1/metabolismo , Sarcoma de Ewing/metabolismo , Factores de Transcripción/metabolismo , Línea Celular Tumoral , Humanos , Modelos Biológicos , Fenotipo , Reacción en Cadena de la Polimerasa , Interferencia de ARN , Proteína EWS de Unión a ARN , Retroviridae/metabolismo , Transducción de Señal , Transcripción Genética , Proteína con Dedos de Zinc GLI1RESUMEN
EWS/FLI and other EWS/ets chimeric transcription factors play a central role in the biology of the Ewing family tumors. As with many oncogenes, EWS/FLI biologic activity can be demonstrated in a limited range of cellular contexts. To investigate the causes of this restriction, we demonstrate that two immortalized fibroblast lines resistant to EWS/FLI transformation, Rat1 and Yal7, express stable levels of EWS/FLI protein. Despite their resistance to EWS/FLI, Rat1 and Yal7 can be transformed by the potent EWS/FLI downstream mediator PDGF-C. In contrast to NIH3T3, the EWS/FLI resistant lines show no upregulation of PDGF-C in response to EWS/FLI, demonstrating differential EWS/FLI function in different cellular backgrounds. This phenomenon of differential function can also be demonstrated for several other NIH3T3 targets of EWS/FLI. Despite the correlation between anchorage-independent growth and PDGF-C induction, PDGF-C does not fully reproduce all aspects of the EWS/FLI phenotype in NIH3T3 cells. These results further point to the importance of PDGF-C in mediating EWS/FLI in vitro transformation and suggest caution in assuming that a transcription factor will produce identical effects in different cellular backgrounds.