RESUMEN
Malignant tumors continue to pose a significant threat to human life and safety and their development is primarily due to the activation of proto-oncogenes and the inactivation of suppressor genes. Among these, the activation of proto-oncogenes possesses greater potential to drive the malignant transformation of cells. Targeting oncogenes involved in the malignant transformation of tumor cells has provided a novel approach for the development of current antitumor drugs. Several preclinical and clinical studies have revealed that the development pathway of B cells, and the malignant transformation of mature B cells into tumors have been regulated by oncogenes and their metabolites. Therefore, summarizing the key oncogenes involved in the process of malignant transformation of mature B cells and elucidating the mechanisms of action in tumor development hold significant importance for the clinical treatment of malignant tumors.
Asunto(s)
Linfocitos B , Neoplasias , Humanos , Proto-Oncogenes/genética , Neoplasias/genéticaRESUMEN
Non-small cell lung cancer (NSCLC) presents the greatest number of identified therapeutic targets, some of which have therapeutic utility. Currently, detecting EGFR, BRAF, KRAS and MET mutations, ALK, ROS1, NTRK and RET translocations, and PD-L1 expression in these patients is considered essential. The use of next-generation sequencing facilitates precise molecular diagnosis and allows the detection of other emerging mutations, such as the HER2 mutation and predictive biomarkers for immunotherapy responses. In this consensus, a group of experts in the diagnosis and treatment of NSCLC selected by the Spanish Society of Pathology and the Spanish Society of Medical Oncology have evaluated currently available information and propose a series of recommendations to optimize the detection and use of biomarkers in daily clinical practice (AU)
Asunto(s)
Humanos , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Proteínas Tirosina Quinasas/genética , Proto-Oncogenes/genética , Sociedades Médicas , Consenso , EspañaRESUMEN
Background The study examines the function of hypoxia-mediated down-regulation of microRNAs (miRNAs) (mir-30c, mir-135a, and mir-27a) in the process of bladder cancer immune escape. Methods Quantitative Real-time PCR (qRT-PCR) was carried out to determine gene expression levels of Drosha and Dicer under hypoxia treatment, while western blotting and flow cytometry were used to determine protein expression. Seven reported miRNAs were identified via qRT-PCR assay. Flow cytometry detection of CD3/CD4/CD8-positive expression and statistics. Enzyme-linked immunosorbent assay (ELISA) detected cellular immune factors content. Cell apoptosis was checked via flow cytometry assay. Luciferase report assay and western blot assays were both used to verify the relationship between miRNAs and Casitas B-lineage lymphoma proto-oncogene b (Cbl-b). The animal model was established and Hematoxylineosin (HE) staining, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and immunohistochemistry (IHC) assays were separately used to verify the conclusions. Results The CD3 + /CD4 + expression was increased in the hypoxia group, while CD3 + /CD8 + expression, the cellular immune factors content Interleukin-2 (IL-2) and Tumor Necrosis Factor-α (TNFα) along with the cell apoptosis were suppressed. The protein expression of Cbl-b was found to be up-regulated in the hypoxia group. After constructing the overexpression/ knockdown of Cbl-b in peripheral blood mononuclear cell (PBMC), Cbl-b has been found to promote tumor immune escape in bladder cancer. Furthermore, Cbl-b had been identified as the co-targets of mir-30c, mir-135a, and mir-27a and down-regulation of miRNA biogenesis promotes Cbl-b expression and deactivating T cells in vitro/in vivo. Conclusion Hypoxia-mediated down-regulation of miRNAs biogenesis promotes tumor immune escape in bladder cancer, which could bring much more advance to the medical research on tumors (AU)
Asunto(s)
Humanos , Regulación hacia Abajo/inmunología , MicroARNs/metabolismo , Escape del Tumor/inmunología , Hipoxia Tumoral/inmunología , Neoplasias de la Vejiga Urinaria/inmunología , Apoptosis , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Interleucina-2/metabolismo , Ratones Endogámicos C57BL , Estudios Prospectivos , Proto-Oncogenes/genética , Distribución Aleatoria , Factor de Necrosis Tumoral alfa/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
Long non-coding RNAs (LncRNAs) are RNA transcripts longer than 200 nucleotides. They are new players in transcriptional regulation and cancer research. LincRNA-p21 is a p53-regulated lncRNA involved in the p53 transcriptional network. It has an important role in regulating cellular proliferation and apoptosis. Chronic lymphocytic leukemia is derived by a typical defect in apoptosis and characterized by clonal proliferation and accumulation of mature B cells. The aim of the present study was to assess the expression pattern of the lincRNA-p21 and investigate its potential role as a new prognostic marker in CLL. Methods The study was conducted on 80 newly diagnosed CLL patients and 80 age- and sex-matched controls. The analysis of LincRNA-p21 and the p53 downstream proapoptotic target genes (MDM2, PUMA, BAX, and NOXA) was performed by real-time PCR. The cytogenetic abrasions and expression of ZAP70 and CD38 were detected by FISH and Flow cytometry, respectively. Results LincRNA-p21 was significantly downregulated in CLL patients compared to controls. The downstream proapoptotic targets were significantly downregulated in CLL patients and positively correlated with lincRNA-p21. Low expression of lincRNA-p21 was associated with poor prognostic markers (advanced stages of CLL, del 17p13, ZAP70, and CD38 expression), failure of complete remission, shorter progression free survival, and overall survival. Low lincRNA-p21 expression was independently prognostic for shorter time to treatment. Conclusion Low expression of lincRNA-p21 demarcates a more aggressive form of CLL with poor prognosis. Therefore, it could be considered as a new prognostic marker to predict disease outcome in CLL (AU)
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Leucemia Linfocítica Crónica de Células B/genética , Proto-Oncogenes/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , ARN Largo no Codificante/genética , Proteína p53 Supresora de Tumor/genética , Pronóstico , Apoptosis/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Estudios de Casos y Controles , Proliferación Celular , Leucemia Linfocítica Crónica de Células B/mortalidadRESUMEN
Background: Next-generation sequencing (NGS) based assay for finding an actionable driver in non-small-cell lung cancer is a less used modality in clinical practice. With a long list of actionable targets, limited tissue, arduous single-gene assays, the alternative of NGS for broad testing in one experiment looks attractive. We report here our experience with NGS for biomarker testing in hundred advanced lung cancer patients. Methods: Predictive biomarker testing was performed using the Ion AmpliSeq™ Cancer Hotspot Panel V2 (30 tumors) and Oncomine™ Solid Tumor DNA and Oncomine™ Solid Tumor Fusion Transcript kit (70 tumors) on IonTorrent sequencing platform. Results: One-seventeen distinct aberrations were detected across 29 genes in eighty-six tumors. The most commonly mutated genes were TP53 (43% cases), EGFR (23% cases) and KRAS (17% cases). Thirty-four patients presented an actionable genetic variant for which targeted therapy is presently available, and fifty-two cases harbored non-actionable variants with the possibility of recruitment in clinical trials. NGS results were validated by individual tests for detecting EGFR mutation, ALK1 rearrangement, ROS1 fusion, and c-MET amplification. Compared to single test, NGS exhibited good agreement for detecting EGFR mutations and ALK1 fusion (sensitivity- 88.89%, specificity- 100%, Kappa-score 0.92 and sensitivity- 80%, specificity- 100%, Kappa-score 0.88; respectively). Further, the response of patients harboring tyrosine kinase inhibitor (TKI) sensitizing EGFR mutations was assessed. The progression-free-survival of EGFR positive patients on TKI therapy, harboring a concomitant mutation in PIK3CAmTOR and/or RAS-RAF-MAPK pathway gene and/or TP53 gene was inferior to those with sole-sensitizing EGFR mutation (2 months vs. 9.5 months, P = 0.015). Conclusions: This is the first study from South Asia looking into the analytical validity of NGS and describing the mutational landscape of lung cancer patients to study the impact of co-mutations on cancer biology and treatment outcome. Our study demonstrates the clinical utility of NGS testing for identifying actionable variants and making treatment decisions in advanced lung cancer
Asunto(s)
Humanos , Masculino , Femenino , Proto-Oncogenes/genética , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares/genética , Mutación/genética , Reproducibilidad de los ResultadosRESUMEN
ABSTRACT Objective: To verify the physiological action of triiodothyronine T3 on the expression of transforming growth factor α (TGFA) mRNA in MCF7 cells by inhibition of RNA Polymerase II and the MAPK/ERK pathway Materials and methods: The cell line was treated with T3 at a physiological dose (10−9M) for 10 minutes, 1 and 4 hour (h) in the presence or absence of the inhibitors, α-amanitin (RNA polymerase II inhibitor) and PD98059 (MAPK/ERK pathway inhibitor). TGFA mRNA expression was analyzed by RT-PCR. For data analysis, we used ANOVA, complemented with the Tukey test and Student t-test, with a minimum significance of 5%. Results: T3 increases the expression of TGFA mRNA in MCF7 cells in 4 h of treatment. Inhibition of RNA polymerase II modulates the effect of T3 treatment on the expression of TGFA in MCF7 cells. Activation of the MAPK/ERK pathway is not required for T3 to affect the expression of TGFA mRNA. Conclusion: Treatment with a physiological concentration of T3 after RNA polymerase II inhibition altered the expression of TGFA. Inhibition of the MAPK/ERK pathway after T3 treatment does not interfere with the TGFA gene expression in a breast adenocarcinoma cell line.
Asunto(s)
Humanos , Femenino , Triyodotironina/genética , Neoplasias de la Mama/genética , Adenocarcinoma/genética , Regulación Neoplásica de la Expresión Génica/genética , Factor de Crecimiento Transformador alfa/genética , Sistema de Señalización de MAP Quinasas/genética , Triyodotironina/metabolismo , Triyodotironina/farmacología , Proto-Oncogenes/genética , Neoplasias de la Mama/metabolismo , ARN Mensajero/genética , Adenocarcinoma/metabolismo , Factor de Crecimiento Transformador alfa/efectos de los fármacos , Factor de Crecimiento Transformador alfa/metabolismo , Línea Celular Tumoral/metabolismo , Células MCF-7/metabolismoRESUMEN
Objective. Recent studies have identified Engrailed-2 (EN-2), a homeobox-containing transcription factor, as a candidate oncogene in prostate cancer (PC). Therapeutic targeting on EN-2, however, is limited because the mechanism underlying EN-2 overexpression in prostatic cancer cells is unknown. This study was to investigate the potential regulatory role of miR-33a on EN-2 expression and explore this signaling axis in ability of prostate cancer survival and metastasis. Methods. The relative expression of miR-33a and EN-2 in paired prostate cancer tissue and adjacent normal tissue as well as in prostate cancer cell lines, PC3 and DU145, was determined using quantitative real-time PCR or western blot, respectively. Cells survival, migration and invasion were evaluated by assays of MTT, TUNEL and Boyden chamber assays, respectively. Direct regulation of EN-2 by miR-33a was examined by luciferase reporter assay. Results. The data showed that miR-33a was upregulated and EN-2 was downregulated in both prostate cancer tissue and prostate cancer cells. miR-33a overexpression suppresses prostate cancer cell survival and metastasis. miR-33a can directly act on EN-2 expression by binding to 3′UTR of its mRNA. Also, miR-33a negatively regulated EN-2 mRNA and protein expression. In pcDNA-EN-2 and miR-33a mimic co-transfected PC3 and DU145 cells, EN-2 overexpression reverses the anti-cell survival and metastasis actions of miR-33a overexpression. The pivotal role of miR-33a in inhibiting prostate tumor growth was confirmed in xenograft models of prostate cancer. Conclusion. Our data suggest that the functional interaction of miR-33a and EN-2 is involved in tumorigenesis of prostate cancer. Also in this process EN-2 serves as a negative responder for miR-33a (AU)
No disponible
Asunto(s)
Humanos , Masculino , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/patología , Metástasis de la Neoplasia/fisiopatología , ARN Mensajero/genética , Proteína de Susceptibilidad a Apoptosis Celular/genética , Movimiento Celular/genética , Biomarcadores de Tumor/genética , Neoplasias de la Próstata/genética , Reacción en Cadena de la Polimerasa/tendencias , ARN Mensajero/metabolismo , Western Blotting , Luciferasas/análisis , Análisis de Varianza , Represión Epigenética/genética , Proto-Oncogenes/genética , Proteínas Oncogénicas/genéticaRESUMEN
No disponible
Asunto(s)
Humanos , Masculino , Anciano , Carcinoma Medular/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasias de la Tiroides/diagnóstico , Síndrome de Cushing/diagnóstico , Cetoconazol/uso terapéutico , Bocio Nodular/diagnóstico , Hormona Adrenocorticotrópica , Calcitonina/sangre , Feocromocitoma , Hiperparatiroidismo , Metanefrina/sangre , Proto-Oncogenes/genética , Tiroidectomía , MutaciónRESUMEN
Las mastocitosis constituyen un grupo heterogéneo de enfermedades caracterizadas por la proliferación clonal de mastocitos en distintos órganos, siendo la localización cutánea la más frecuente. Es «una enfermedad rara o poco frecuente», y afecta a todos los grupos de edad, si bien suele aparecer en la primera década de la vida o entre la segunda y la quinta década de la vida, con una distribución similar por sexos. En los últimos años se han realizado grandes avances en el conocimiento fisiopatogénico del trastorno: las mutaciones somáticas del gen c-kit y la presencia de alteraciones inmunofenotípicas en los mastocitos son elementos importantes en la fisiopatogenia de las mastocitosis. Las manifestaciones clínicas son variadas y las lesiones cutáneas son la clave diagnóstica en la mayoría de los pacientes
Mastocytosis is a term used to describe a heterogeneous group of disorders characterized by clonal proliferation of mast cells in various organs. The organ most often affected is the skin. Mastocytosis is a relatively rare disorder that affects both sexes equally. It can occur at any age, although it tends to appear in the first decade of life, or later, between the second and fifth decades. Our understanding of the pathophysiology of mastocytosis has improved greatly in recent years, with the discovery that somatic c-kit mutations and aberrant immunophenotypic features have an important role. The clinical manifestations of mastocytosis are diverse, and skin lesions are the key to diagnosis in most patient
Asunto(s)
Humanos , Masculino , Femenino , Mastocitosis/complicaciones , Mastocitosis/diagnóstico , Mastocitosis/fisiopatología , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/fisiopatología , Mastocitosis Cutánea/diagnóstico , Mastocitosis Cutánea/fisiopatología , Urticaria Pigmentosa/complicaciones , Triptasas , Urticaria Pigmentosa/diagnóstico , Urticaria Pigmentosa/fisiopatología , Mastocitos/citología , Mastocitos/patología , Proto-Oncogenes/genética , Valor Predictivo de las Pruebas , Inmunohistoquímica/métodosRESUMEN
OBJETIVO: El carcinoma medular de tiroides es un tumor de baja prevalencia cuyo pronóstico es peor que el del cáncer diferenciado de tiroides debido su mayor agresividad. El objetivo de este trabajo es describir las características demográficas, clínicas y genéticas de los pacientes atendidos en el área sanitaria de la Comunidad de Castilla-La Mancha durante 16 años. PACIENTES Y MÉTODOS: Los datos se recogieron mediante revisión de historias clínicas. RESULTADOS: Se revisaron las historias clínicas de 58 pacientes con una edad media al diagnóstico de 51 años (intervalo de 6 a 82 años) y un 63,8% de mujeres. La prevalencia fue de 2,84 casos por 100.000 habitantes, con una gran variabilidad entre áreas (de 0 a 5,4 casos por 100.000 habitantes). Los casos familiares representaron el 34,5% del total, siendo la mutación más frecuente la C634Y. El motivo más frecuente de diagnóstico fue la palpación de un bultoma cervical (70,6%); se solicitó ecografía al diagnóstico en 56 de 58 casos, y la calcitonina en 8 de 58 casos. La multicentricidad del tumor fue descrita en el 59 y 50% de los casos de síndrome de neoplasia endocrina múltiple tipo 2A y 2B, respectivamente, y en ningún caso esporádico. El 52% de los pacientes presentaba un estadio avanzado al diagnóstico (III o IV). La mediana de seguimiento fue de 36 meses (rango intercuartílico 14-210), con la pérdida de 11 pacientes durante el seguimiento. CONCLUSIONES: El diagnóstico de carcinoma medular de tiroides en Castilla-La Mancha se basa en la ecografía cervical, pero no en la calcitonina. Existe una alta prevalencia de este carcinoma, tanto familiar como esporádico, y una importante variabilidad en el tipo de mutación del protooncogén rearranged during transfection comparadas con las del resto de la población española
OBJECTIVE: Medullary thyroid cancer is a rare tumor that is more aggressive and has a worse prognosis than differentiated thyroid cancer. The purpose of this study was to report the demographic, clinical, and genetic characteristics of patients seen in the health care system of the community of Castilla-La Mancha over a 16-year period. PATIENTS AND METHODS: Data were collected through a review of patients' medical records. RESULTS: The medical records of 58 patients (mean age at diagnosis, 51 years; range, 6-82 years; 63.8% women) were reviewed. Prevalence rate was 2.84 cases per 100,000 inhabitants, with a high variability between areas (range, 0-5.4 cases per 100,000 inhabitants). Familial cases accounted for 34.5% of all medullary thyroid cancers, and the most common mutation was C634Y. The condition was most commonly diagnosed following palpation of a cervical lump (70.6%). At diagnosis, 56 of 58 patients underwent ultrasound and 8 of 58 patients were tested for serum calcitonin. Tumor multicentricity was reported in 59 and 50% of patients with multiple endocrine neoplasia syndrome type 2A and 2B, respectively, and in no sporadic cases. Fifty-two percent of patients had an advanced stage (III or IV) at diagnosis. Median follow-up was 36 months (interquartile range, 14-210); 11 patients were lost to follow-up. CONCLUSIONS: In Castilla-La Mancha, medullary thyroid cancer is diagnosed by cervical ultrasound, rather than calcitonin assay. There is a high prevalence of both familial and sporadic medullary thyroid cancer, and a significant variability in the type of proto-oncogen rearranged during transfection mutation as compared to the rest of the Spanish population
Asunto(s)
Humanos , Carcinoma Medular/epidemiología , Neoplasias de la Tiroides/epidemiología , Tiroidectomía/estadística & datos numéricos , Neoplasia Endocrina Múltiple Tipo 2a/epidemiología , Transfección , Proto-Oncogenes/genética , Marcadores Genéticos , Estudios Retrospectivos , Nódulo Tiroideo/patologíaRESUMEN
Melanoma is the deadliest cutaneous malignancy and its incidence continues to grow. Until 2011, the treatment options for metastatic melanoma were scarce and without any overall survival benefit. The emergence of new targeted therapies for BRAF mutant melanoma (vemurafenib) and immunotherapy (ipilimumab) has changed the standard of care for this disease. The objective of the present review is to summarise the biological background of the new therapeutic approaches in melanoma, focusing on apoptosis resistance, immune modulation and angiogenesis, and the direct translation into clinical practice (AU)
Asunto(s)
Humanos , Masculino , Femenino , Antineoplásicos/uso terapéutico , Inmunoterapia/métodos , Inmunoterapia , Melanoma/terapia , Neoplasias Cutáneas/terapia , Proteínas Proto-Oncogénicas B-raf , Proteínas Proto-Oncogénicas B-raf/genética , Inhibidores de la Angiogénesis/uso terapéutico , Apoptosis , Melanoma/inmunología , Melanoma/metabolismo , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Biomarcadores de Tumor/metabolismo , Proto-Oncogenes/genéticaRESUMEN
A hereditariedade autossômica dominante da neoplasia endócrina múltipla tipo 2 (NEM 2) relaciona-se à ativação do proto-oncogene RET, através de mutações missense. As mutações do RET são encontradas em 95% dos casos índices de NEM 2 e apresentam relação direta entre sua localização codon específica e os diversos fenótipos desenvolvidos, dentre eles, carcinoma medular datireóide, feocromocitoma e/ou hiperparatireoidismo. Baseando-se em análises bioquímicas e genéticas, é possível efetuar um diagnósticoprematuro, viabilizando a intervenção cirúrgica em tempo hábil. A periodicidade da monitorização bioquímica é ditada pelo fenótipopresente, pelas manifestações clínicas familiares e pelo genótipo RET. A recomendação da análise genética deve ser feita a todos indivíduos afetados e também a seus ascendentes e descendentes diretos, caso alguma mutação esteja presente; permitindo identificar os portadores de mutações RET, previamente ao início da sintomatologia. Neste trabalho, serão discutidos os aspectos molecularesdos diversos fenótipos da NEM 2, bem como a importância da identificação genotípica do proto-oncogene RET e sua interação com os testes bioquímicos visando o diagnóstico precoce, prevenção, monitorização, screening familiar e, portanto, maior sobrevidado paciente.
The dominant autossomic hereditarity of the multiple endocrine neoplasia type 2 (MEN 2) is related to RET proto-oncogene activation, through mutations missense. RET mutations are found in 95% of MEN 2 index cases and present direct relation between its specific localization codon and the diverse developed phenotypes, among them, medullary thyroid carcinoma, pheochromocytoma and/or hyperparathyroidism. Being based on biochemists and genetics analyses, it is possible to perform a premature diagnosis, making possible a surgical intervention in the right time. The biochemist monitoring regularity is determined by present phenotype, the familiar clinical manifestations and RET genotype. The recommendation of the genetic analysis must be made to all affected individuals and also their ascendants and descendants, in case some mutation is present, allowing to identify the RET mutations carriers previously to the beginning of the symptomatology. In this work, the molecular aspects of MEN 2 diverse phenotypes will be discussed, as well as the importance of the RET proto-oncogene genotypic identification and its interaction with the biochemists tests aiming the precocious diagnosis, prevention, monitoring, familiar screening e, therefore, the patients longer survival.
Asunto(s)
Humanos , Carcinoma Medular , Genética Médica , Hiperparatiroidismo , Herencia/genética , Feocromocitoma , Proto-Oncogenes/genéticaRESUMEN
El carcinoma medular de tiroides (CMT) puede presentarse en forma esporádica o familiar, en cuyo caso se integra en la neoplasia endocrina múltiple tipo 2 (NEM 2). La NEM 2 se origina como consecuencia de mutaciones germinales en el gen RET. Este gen incluye 21 exones y codifica el receptor RET, un receptor de membrana citoplasmática con actividad tirosinacinasa. La peculiaridad de esta alteración reside en la posibilidad de establecer una relación genotipo-fenotipo. Las distintas mutaciones en los codones del gen RET dan lugar a diversos cuadros clínicos, etiquetados clásicamente como NEM 2A, NEM 2B y CMTF (CMT familiar). En los últimos años se ha añadido una nueva clasificación en función de la agresividad del comportamiento tumoral, en la que se distinguen 3 niveles de riesgo. En la presente revisión exponemos las características fisiológicas y patológicas del gen RET, la relación genotipo-fenotipo tanto clásica como por grados de agresividad, los elementos posiblemente modificadores en esa relación (polimorfismos de un único nucleótido), la actitud a adoptar ante el CMT y el tratamiento recomendado según las características genéticas (AU)
Medullary thyroid carcinoma (MTC) can be sporadic or hereditary. The hereditary form of MTC is classified as multiple endocrine neoplasia type 2 (MEN 2). MEN 2 syndromes are caused by germinal mutations in the RET proto-oncogene. The RET gene includes 21 exons and encodes a plasma membrane-bound tyrosine kinase enzyme, the RET receptor. The peculiarity of this disease lies in the possibility of establishing genotype-phenotype correlations. Distinct RET codon mutations give rise to the different MEN 2 syndromes, traditionally classified as MEN 2A, MEN 2B and familial MTC. In the last few years, a new classification has been suggested, based on biologic tumoral aggressiveness, in which RET mutations are stratified into three levels of risk. In this review, we explain the physiological and pathological features of the RET gene, genotype-phenotype correlations (both traditional and the new risk classification), the elements that may modify this relationship (such as single nucleotide polymorphisms), suggested clinical decision-making in MTC and genetically-based treatment (AU)
Asunto(s)
Humanos , Carcinoma Medular/genética , Neoplasias de la Tiroides/genética , Neoplasia Endocrina Múltiple/genética , Genotipo , Fenotipo , Proto-Oncogenes/genéticaRESUMEN
A neoplasia endócrina múltipla tipo 2 é uma síndrome tumoral hereditária, onde o RET apresenta mutações germinativas causadoras da patologia. Com o diagnóstico genético, a tireoidectomia total tornou-se curativa para indivíduos assintomáticos portadores de mutações. Nosso objetivo é validar a metodologia de eletroforese em gel sensível à conformação (CSGE) no rastreamento de mutações do RET, comparativamente ao polimorfismo conformacional de cadeia simples (SSCP) e seqüenciamento genético em famílias portadoras das mutações: Cys620Arg (NEM-2A + HSCR e CMT-F); Cys634Arg (NEM-2A); Cys634Tyr (CMT-F); Val648Ile (NEM-2A); Val804Met (CMT-F) e Met918Thr (NEM-2B). Os polimorfismos rastreados foram: Gly691Ser, Leu769Leu e Ser904Ser. Ambas metodologias de rastreamento demonstraram-se sensíveis para alterações genéticas do RET exceto para a mutação Val804Met e polimorfismo Ser904Ser.
Multiple endocrine neoplasia type 2 (MEN-2) is inherited tumor syndrome, presenting RET germline mutations as causing-disease. With genetic diagnosis, prophylactic total thyroidectomy became curative for asymptomatic individuals carrying RET mutations. Our objective is to validate conformation sensitive gel electrophoresis (CSGE) methodology for RET genetic screening mutation, comparatively to single-strand conformation polymorphism (SSCP) and automatic sequencing in mutations carrying families: Cys620Arg (MEN-2A + HSCR and FMTC); Cys634Arg (MEN-2A); Cys634Tyr (FMTC); Val648Ile (MEN-2A); Val804Met (FMTC) and Met918Thr (MEN-2B). Polymorphisms were also screened: Gly691Ser, Leu769Leu and Ser904Ser. Both screening methodologies were sensible for RET genetic alterations except for Val804Met mutation and Ser904Ser polymorphism.
Asunto(s)
Humanos , Carcinoma Medular/genética , /genética , Neoplasias de la Tiroides/diagnóstico , Análisis Mutacional de ADN/métodos , Electroforesis/métodos , Mutación/genética , /genética , Proto-Oncogenes/genética , Reacción en Cadena de la Polimerasa/métodosRESUMEN
The aims of this study were to estimate the incidences of BCR/ABL, MLL, TEL/AML1 rearrangements, and p16 deletions in childhood acute lymphoblastic leukemia (ALL), to identify new abnormalities, and to demonstrate the usefulness of interphase fluorescence in situ hybridization (FISH). We performed G-banding analysis and FISH using probes for BCR/ABL, MLL, TEL/AML1 rearrangements, and p16 deletions on 65 childhood ALL patients diagnosed and uniformly treated at a single hospital. Gene rearrangements were identified in 73.8% of the patients using the combination of G-banding and FISH, while the chromosomal abnormalities were identified in 49.2% using G-banding alone. Gene rearrangements were disclosed by FISH in 24 (72.7%) of 33 patients with normal karyotype or no mitotic cell in G-banding. Among the gene rearrangements detected by FISH, the most common gene rearrangement was p16 deletion (20.3%) and the incidences of others were 14.1% for TEL/AML1, 11.3% for MLL, and 1.8% for BCR/ABL translocations. Infrequent or new aberrations such as AML1 amplification, MLL deletion, ABL deletion, and TEL/AML1 fusion with AML1 deletion were also observed. We established the rough incidences of gene rearrangements in childhood ALL, found new abnormalities and demonstrated the diagnostic capability of interphase FISH to identify cryptic chromosome aberrations.
Asunto(s)
Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Aberraciones Cromosómicas , Bandeo Cromosómico , Proteínas de Unión al ADN/genética , Proteínas de Fusión bcr-abl/genética , Eliminación de Gen , Reordenamiento Génico , Hibridación Fluorescente in Situ , Interfase , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas de Fusión Oncogénica/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proto-Oncogenes/genética , Factores de Transcripción/genética , Resultado del TratamientoRESUMEN
OBJECTIVE@#To screen the differential expression of oncogenes and tumors suppressed genes(OTS genes) after human brain contusion by cDNA microrarray.@*METHODS@#The total RNAs isolated from normal and contusion human brain tissues were purified by Oligotex to obtain mRNAs. Both sources of mRNAs were reversely transcribed to cDNAs with the incorporation of fluorescent dUTP to prepare the hybridization probes. The probe from normal tissue and the contusion brain tissue were labeled with Cy3-dUTP and Cy5-dUTP respectively. The mixed probes were hybridized to the BioDoor Chip OTS-2.2S, a cDNA microarray which contains 227 oncogenes and tumors suppressed genes. After high-stringent washing, the cDNA microarray was scanned for the fluorescent signals and showed differences between two tissues.@*RESULTS@#Among the 227 target genes, 3 genes including Human carcinoma associated HOJ-1 (HoJ-1), Human KIAAOO65 gene,Human retinoblastoma related protein (p107) gene, showed distinct deference in expression level between the human brain contusion tissue and normal tissue.@*CONCLUSION@#The 3 genes in the brain contusion was significantly the differential expression by OTS 2.2S cDNA microarray. Further analysis of these genes will be helpful to understand the molecular mechanism of brain injury and utilization in forensic medicine.
Asunto(s)
Humanos , Lesiones Encefálicas/patología , Perfilación de la Expresión Génica , Marcadores Genéticos , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas/genética , Proto-Oncogenes/genética , ARN Mensajero/biosíntesis , Proteína p107 Similar a la del Retinoblastoma/genéticaRESUMEN
Los proto-oncogenes desempeñan un papel clave en la regulación de la proliferación y diferenciación celular, junto con genes supresores, genes de reparación del ADN y genes reguladores de la apoptosis, fundamentalmente. La acumulación de sucesivas alteraciones cualitativas y/o cuantitativas de estos genes constituye la base del desarrollo del cáncer. La sobreexpresión de proto-oncogenes constituye un importante mecanismo de activación oncogénica al representar una ganancia de función y, por tanto, la estimulación de la proliferación o la supervivencia celular. La sobreexpresión génica puede estar asociada a cambios genéticos, tales como la translocación cromosómica o la amplificación génica, o a cambios epigenéticos, consistentes principalmente en alteraciones de los patrones de metilación del ADN y acetilación de las histonas. Dicha alteración es frecuente en cáncer de mama y se asocia a factores de mal pronóstico y resistencia al tratamiento. (AU)
Asunto(s)
Femenino , Humanos , Expresión Génica , Neoplasias de la Mama/genética , Proto-Oncogenes/genética , Pronóstico , Regulación de la Expresión GénicaRESUMEN
La pleiotrofina (PTN) es un factor de crecimiento perteneciente a una familia de proteínas homólogas a las HBGF. El gen Ptn se expresa ampliamente durante el desarrollo mientras que en la vida adulta su distribución es muy restringida. Pero su expresión aumenta en los procesos tumorales e inflamatorios crónicos. El propósito de este artículo es realizar una revisión y análisis de los conocimientos actuales sobre la PTN, con especial interés en sus propiedades como factor promotor del crecimiento celular y la angiogénesis (AU)
Asunto(s)
Humanos , División Celular/fisiología , Factores de Crecimiento de Fibroblastos/fisiología , Neovascularización Fisiológica/fisiología , Citocinas/fisiología , Citocinas/genética , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/química , Neoplasias/genética , Proto-Oncogenes/genéticaRESUMEN
El cáncer es un proceso multifactorial y con múltiples etapas. Los protooncogenes, antioncogenes y virus oncogénicos están involucrados en el desarrollo de diversas neoplasias. La expresión alterada de los protooncogenes (por mutaciones, rearreglos o amplificaciones), así como la cooperación entre ellos puede llevar a la célula a una estado transformado. Los genes p53 y RB codifican para dos proteínas antioncogénicas que regulan las decisiones celulares de proliferación o diferenciación. La ausencia de RB (pérdida de ambos alelos) lleva a la liberación de factores de transcripción. p53 en su forma mutada, favorece el crecimiento celular. El cáncer cervicouterino ejemplifica claramente la intervención de este tipo de factores en su desarrollo. Los papilomavirus humanos genitales (PVH) estan implicados en su etiología como iniciadores de la proliferación celular. La inactivación de las proteínas antioncogénicas p53 y p105 RB porparte de los oncogenes virales E6 y E7, respectivamente, mantiene el estado de divición celular continua. Adicionalmente, la participación de ooncogenes expresados en forma alterada (c-myc) y otros cofactores contribuyen a modificar los periodos de latencia y la gravedad de la enfermedad
Asunto(s)
Factores de Transcripción/genética , Genes Supresores de Tumor/genética , Oncogenes/genética , Papillomaviridae/genética , Papillomaviridae/ultraestructura , Proto-Oncogenes/genética , Transformación Celular Viral/genética , Neoplasias del Cuello Uterino/genética , Análisis Mutacional de ADN , ADN Viral/ultraestructura , Genes myc , Genes rasRESUMEN
En el siguiente trabajo de revisión, se exponen los aspectos más relevantes acerca de los oncogenes y el papel que éstos juegan en la aparición y desarrollo del cáncer. Para abordar esta novedosa temática, se comenzó definiendo los novedosos conceptos de protooncogen y oncogen, así como una clasificación de los productos proteicos de éstos y las funciones que desempeñan dentro de la célula, en el control de los procesos de proliferación y diferenciación. A continuación se explica de forma breve, los mecanismos mediante los cuales ocurren cada una de las alteraciones que tienen lugar en los oncogenes y las asociaciones establecidas entre éstos con las diferentes patologías. Finalmente se explica con detalles las aplicaciones del conocimiento de los oncogenes en el diseño de nuevas terapias que actúen de forma específica y dejen atrás los efectos indeseables de las terapia convencionales(AU)