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1.
J Hum Genet ; 65(2): 165-174, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31772335

RESUMO

Somatic mutational mosaicism is a common feature of monogenic genetic disorders, particularly in diseases such as retinoblastoma, with high rates of de novo mutations. The detection and quantification of mosaicism is particularly relevant in these diseases, since it has important implications for genetic counseling, patient management, and probably also on disease onset and progression. In order to assess the rate of somatic mosaicism (high- and low-level mosaicism) in sporadic retinoblastoma patients, we analyzed a cohort of 153 patients with sporadic retinoblastoma using ultra deep next-generation sequencing. High-level mosaicism was detected in 14 out of 100 (14%) bilateral patients and in 11 out of 29 (38%) unilateral patients in whom conventional Sanger sequencing identified a pathogenic mutation in blood DNA. In addition, low-level mosaicism was detected in 3 out of 16 (19%) unilateral patients in whom conventional screening was negative in blood DNA. Our results also reveal that mosaicism was associated to delayed retinoblastoma onset particularly in unilateral patients. Finally we compared the level of mosaicism in different tissues to identify the best DNA source to identify mosaicism in retinoblastoma patients. In light of these results we recommended analyzing the mosaic status in all retinoblastoma patients using accurate techniques such as next-generation sequencing, even in those cases in which conventional Sanger sequencing identified a pathogenic mutation in blood DNA. Our results suggest that a significant proportion of those cases are truly mosaics that could have been overlooked. This information should be taking into consideration in the management and genetic counseling of retinoblastoma patients and families.

2.
Blood ; 135(4): 274-286, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31738823

RESUMO

Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.

3.
Haematologica ; 104(9): 1822-1829, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30733272

RESUMO

Burkitt-like lymphoma with 11q aberration is characterized by pathological features and gene expression profile resembling those of Burkitt lymphoma but lacks the MYC rearrangement and carries an 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized entities is controversial. To improve the understanding of Burkitt-like lymphoma with 11q aberration we performed an analysis of copy number alterations and targeted sequencing of a large panel of B-cell lymphoma-related genes in 11 cases. Most patients had localized nodal disease and a favorable outcome after therapy. Histologically, they were high grade B-cell lymphoma, not otherwise specified (8 cases), diffuse large B-cell lymphoma (2 cases) and only one was considered as atypical Burkitt lymphoma. All cases had a germinal center B-cell signature and phenotype with frequent LMO2 expression. The patients with Burkitt-like lymphoma with 11q aberration had frequent gains of 12q12-q21.1 and losses of 6q12.1-q21, and lacked common Burkitt lymphoma or diffuse large B-cell lymphoma alterations. Potential driver mutations were found in 27 genes, particularly involving BTG2, DDX3X, ETS1, EP300, and GNA13 However, ID3, TCF3, or CCND3 mutations were absent in all cases. These results suggest that Burkitt-like lymphoma with 11q aberration is a germinal center-derived lymphoma closer to high-grade B-cell lymphoma or diffuse large B-cell lymphoma than to Burkitt lymphoma.

4.
Cell Mol Life Sci ; 76(11): 2231-2243, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30770954

RESUMO

Current therapies for most non-infectious diseases are directed at or affect functionality of the human translated genome, barely 2% of all genetic information. By contrast, the therapeutic potential of targeting the transcriptome, ~ 70% of the genome, remains largely unexplored. RNA therapeutics is an emerging field that widens the range of druggable targets and includes elements such as microRNA. Here, we sought to screen for microRNA with tumor-suppressive functions in neuroblastoma, an aggressive pediatric tumor of the sympathetic nervous system that requires the development of new therapies. We found miR-323a-5p and miR-342-5p to be capable of reducing cell proliferation in multiple neuroblastoma cell lines in vitro and in vivo, thereby providing a proof of concept for miRNA-based therapies for neuroblastoma. Furthermore, the combined inhibition of the direct identified targets such as CCND1, CHAF1A, INCENP and BCL-XL could reveal new vulnerabilities of high-risk neuroblastoma.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias do Sistema Nervoso/genética , Neuroblastoma/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Criança , Fator 1 de Modelagem da Cromatina/genética , Fator 1 de Modelagem da Cromatina/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Neoplasias do Sistema Nervoso/mortalidade , Neoplasias do Sistema Nervoso/patologia , Neoplasias do Sistema Nervoso/terapia , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Neuroblastoma/terapia , Neurônios/metabolismo , Neurônios/patologia , Ligação Proteica , Transdução de Sinais , Análise de Sobrevida , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
5.
Exp Mol Med ; 50(4): 51, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29700278

RESUMO

Approximately 15,000 new cases of pediatric cancer are diagnosed yearly in Europe, with 8-10% corresponding to neuroblastoma, a rare disease with an incidence of 8-9 cases per million children <15 years of age. Although the survival rate for low-risk and intermediate-risk patients is excellent, half of children with high-risk, refractory, or relapsed tumors will be cured, and two-thirds of the other half will suffer major side effects and life-long disabilities. Epigenetic therapies aimed at reversing the oncogenic alterations in chromatin structure and function are an emerging alternative against aggressive tumors that are or will become resistant to conventional treatments. This approach proposes targeting epigenetic regulators, which are proteins that are involved in the creation, detection, and interpretation of epigenetic signals, such as methylation or histone post-translational modifications. In this review, we focused on the most promising epigenetic regulators for targeting and current drugs that have already reached clinical trials.

6.
An. pediatr. (2003. Ed. impr.) ; 87(3): 155-163, sept. 2017. tab
Artigo em Espanhol | IBECS | ID: ibc-166299

RESUMO

Introducción: El cáncer es la primera causa de muerte por enfermedad entre el primer año de vida y la adolescencia. Algunos tipos de enfermedad siguen constituyendo un reto en términos de curación. Existe por tanto una necesidad imperiosa de nuevos fármacos. Algunos descubrimientos recientes en la biología del cáncer abren la puerta al desarrollo de terapias dirigidas contra alteraciones moleculares concretas e inmunoterapia. Esto se ha traducido en resultados prometedores sobre todo en oncología de adultos, y en menor medida todavía en niños. Presentamos la actividad en ensayos clínicos precoces (fase I-II) en oncología pediátrica en España. Material y métodos: A través de la Sociedad Española de Oncología y Hematología Pediátrica (SEHOP) contactamos a sus miembros para identificar los ensayos fase I-II en cáncer pediátrico abiertos entre 2005 y 2015. Resultados: En este periodo se abrieron 30 ensayos: 21 (70%) en tumores sólidos y 9 (30%) en hemopatías malignas y se incluyó a 212 pacientes. La mayoría están promovidos por la industria farmacéutica (53%). Desde 2010, 4 centros se han integrado en el consorcio internacional ITCC cuyo objetivo es desarrollar nuevas terapias en cáncer infantil. Esto ha permitido ampliar el abanico de posibilidades terapéuticas. Los resultados de ensayos clínicos terminados muestran la contribución de los investigadores españoles, la introducción de terapias dirigidas y sus beneficios. Conclusiones: La actividad en ensayos clínicos precoces ha aumentado en estos años. La SEHOP está comprometida a desarrollar y participar en ensayos clínicos académicos colaborativos, que favorezcan el avance en las terapias frente al cáncer infantil (AU)


Introduction: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. Material and methods: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. Results: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. Conclusions: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer (AU)


Assuntos
Humanos , Criança , Drogas em Investigação , Avaliação de Medicamentos/tendências , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Ensaios Clínicos como Assunto/estatística & dados numéricos , Medicina de Precisão/tendências
7.
An Pediatr (Barc) ; 87(3): 155-163, 2017 Sep.
Artigo em Espanhol | MEDLINE | ID: mdl-28279690

RESUMO

INTRODUCTION: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. MATERIAL AND METHODS: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. RESULTS: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. CONCLUSIONS: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer.


Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Neoplasias/tratamento farmacológico , Criança , Ensaios Clínicos como Assunto/métodos , Humanos , Espanha , Fatores de Tempo
11.
Med Clin (Barc) ; 126(11): 401-5, 2006 Mar 25.
Artigo em Espanhol | MEDLINE | ID: mdl-16595082

RESUMO

BACKGROUND AND OBJECTIVE: Retinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumor in children and a potential cause of blindness from therapeutic eye ablation, second tumors in germ line mutation carriers, and even death when untreated. The molecular scanning of RB1 in search of germ line mutations in 213 retinoblastoma patients from Spain, Cuba, Colombia and Serbia, has led to the detection of 106 mutations whose knowledge is important for genetic counselling and characterization of phenotypic-genotypic relations. PATIENTS AND METHOD: Mutational study (PCR-sequentiation and microsatellites analysis) in patients with retinoblastoma, from Spain, Cuba, Colombia and Serbia. RESULTS: 45% of mutations, including most of the frame shift (FS), missense (MS) and splicing (SP), were new, while all nonsense mutations (NS) corresponded to hypermutable sites in RB1. Germ line mutations were found in 22% of unilateral sporadic patients. The incidence of SP plus MS mutations in this group of patients was greater (p = 0.018) than in bilateral patients. The frequency of SP mutations was higher (p = 0.0003) in Spain and France than in Germany and United Kingdom, while the incidence of NS mutations was lower (p = 0.0006). SP mutations were associated with the low penetrance phenotype and were also overrepresented (p = 0.018) in patients with delayed retinoblastoma onset. CONCLUSIONS: Mutational scanning of unilateral patients is important for genetic counselling and may help decipher the molecular mechanisms leading to low penetrance or expressivity. The functional characterization of mutations associated with low-penetrance or expressivity phenotypes and the molecular classification of tumors using multiple expression profiling is important for a better understanding of the retinoblastoma pathogenesis.


Assuntos
Aconselhamento Genético , Mutação , Proteína do Retinoblastoma/genética , Retinoblastoma/epidemiologia , Retinoblastoma/genética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Linhagem
12.
Med. clín (Ed. impr.) ; 126(11): 401-405, mar. 2006. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-043842

RESUMO

Fundamento y objetivo: El retinoblastoma, prototipo de cáncer hereditario, puede causar ceguera, por enucleación terapéutica, segundos tumores en pacientes con mutación germinal e incluso muerte si no se trata. El diagnóstico molecular de 213 pacientes a lo largo de 5 años ha conducido a la detección de 106 mutaciones que se analizan desde la perspectiva de la epidemiología molecular y consejo genético. Pacientes y método: Estudio mutacional (reacción en cadena de la polimerasa, secuenciación y análisis de microsatélites) en pacientes con retinoblastoma procedentes de España, Cuba, Colombia y Serbia. Resultados: Un 45% de las mutaciones analizadas son nuevas y corresponden a mutaciones de tipo de corrimiento de pauta de lectura, cambio de aminoácido o procesado del ácido ribonucleico. Todas las mutaciones sin sentido corresponden a sitios de alta mutabilidad. La tasa de detección de mutaciones en pacientes unilaterales esporádicos es alta (22%). En este grupo de pacientes se detecta una mayor incidencia (p = 0,018) de mutaciones de cambio de aminoácido y procesamiento. España y Francia muestran una incidencia mayor de mutaciones del procesado (p = 0,0003) que Alemania y el Reino Unido, países en los que predominan las mutaciones sin sentido (p = 0,0006). Las mutaciones del procesado se asocian al fenotipo de baja penetración y retraso en la aparición de tumores (p = 0,018). Conclusiones: La incidencia de mutaciones germinales en pacientes unilaterales y las relaciones fenotipo/genotipo analizadas indican la necesidad del consejo genético basado en el diagnóstico molecular temprano. La mejora de las técnicas diagnósticas, la caracterización funcional de mutaciones asociadas a baja penetrancia o expresividad y el estudio del transcriptoma de los tumores son objetivos necesarios para definir mejor la patogenia del retinoblastoma


Background and objective: Retinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumor in children and a potential cause of blindness from therapeutic eye ablation, second tumors in germ line mutation carriers, and even death when untreated. The molecular scanning of RB1 in search of germ line mutations in 213 retinoblastoma patients from Spain, Cuba, Colombia and Serbia, has led to the detection of 106 mutations whose knowledge is important for genetic counselling and characterization of phenotypic-genotypic relations. Patients and method: Mutational study (PCR-sequentiation and microsatellites analysis) in patients with retinoblastoma, from Spain, Cuba, Colombia and Serbia. Results: 45% of mutations, including most of the frame shift (FS), missense (MS) and splicing (SP), were new, while all nonsense mutations (NS) corresponded to hypermutable sites in RB1. Germ line mutations were found in 22% of unilateral sporadic patients. The incidence of SP plus MS mutations in this group of patients was greater (p = 0.018) than in bilateral patients. The frequency of SP mutations was higher (p = 0.0003) in Spain and France than in Germany and United Kingdom, while the incidence of NS mutations was lower (p = 0.0006). SP mutations were associated with the low penetrance phenotype and were also overrepresented (p = 0.018) in patients with delayed retinoblastoma onset. Conclusions: Mutational scanning of unilateral patients is important for genetic counselling and may help decipher the molecular mechanisms leading to low penetrance or expressivity. The functional characterization of mutations associated with low-penetrance or expressivity phenotypes and the molecular classification of tumors using multiple expression profiling is important for a better understanding of the retinoblastoma pathogenesis


Assuntos
Humanos , Retinoblastoma/diagnóstico , Epidemiologia Molecular/métodos , Neoplasias da Retina/genética , Retinoblastoma/genética , Genes do Retinoblastoma/genética , Técnicas de Diagnóstico Molecular/métodos , Aconselhamento Genético/métodos , Mutação/genética
13.
J Cancer Res Clin Oncol ; 132(6): 356-62, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16435141

RESUMO

PURPOSE: To assess if molecular detection of minimal disseminated disease by real-time reverse transcription and polymerase chain reaction (RT-PCR) could contribute to a better treatment stratification in patients with rhabdomyosarcoma (RMS). METHODS: Relative quantification of the tumor-mRNA present in serial samples of bone marrow (BM) and peripheral blood (PB) from 16 patients with RMS (7 alveolar and 9 embryonal) was performed by a real-time RT-PCR assay. Expression of MyoD1 and acetylcholine receptor (AChR) was analyzed in all samples, along with PAX3/7-FKHR in samples from alveolar tumors. RESULTS: A good correlation was found between the expression of PAX3/7-FKHR and AChR, while MyoD1 was more sensitive but less specific. In this study, patients with positive PB at the end of treatment showed a poorer prognosis than patients with negative PB. Moreover, in this patient cohort, metastatic relapses were preceded by the detection of microcirculating disease in all cases. CONCLUSION: The detection of minimal circulating and micrometastatic disease by real-time RT-PCR, based on the expression of multiple genes, yields highly reproducible results. Patients with positive PB after treatment show poorer survival than patients without microcirculating disease.


Assuntos
Neoplasias da Medula Óssea/diagnóstico , Neoplasias da Medula Óssea/secundário , Células Neoplásicas Circulantes , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Rabdomiossarcoma Alveolar/diagnóstico , Rabdomiossarcoma Embrionário/diagnóstico , Adolescente , Biomarcadores Tumorais/genética , Neoplasias da Medula Óssea/genética , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Proteína MyoD/genética , Estadiamento de Neoplasias , Neoplasia Residual , Células Neoplásicas Circulantes/metabolismo , Proteínas de Fusão Oncogênica/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores Nicotínicos/genética , Recidiva , Estudos Retrospectivos , Rabdomiossarcoma Alveolar/sangue , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Embrionário/sangue , Rabdomiossarcoma Embrionário/genética , Sensibilidade e Especificidade , Taxa de Sobrevida
14.
Oncol Rep ; 14(4): 1021-7, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16142367

RESUMO

Molecular detection of microcirculating or microdisseminated disease (MDD) with a sensitive methodology could contribute to a better treatment for children with neuroblastoma. To detect circulating neuroblastoma cells, we developed a quantitative assay for the analysis of tyrosine hydroxylase (TH) gene expression. We analyzed 155 samples of peripheral blood (PB) from 25 patients with neuroblastoma in advanced stages (8 stage III and 17 stage IV). TH mRNA was analyzed by RT-PCR assay using TaqMan technology. PB samples (n=25) from donors were used for normalizing TH, and values <7 were considered negative. With a median follow-up of 40 months (range 15-73 months), 9 patients relapsed and 8 patients died of progressive disease. TH expression was detected in the PB of 16 patients (64%) at diagnosis. During treatment, 10 patients had positive samples and 9 patients were still positive for circulating tumor cells at the end of treatment. Actuarial 3-year event-free survival of patients with PB positive for TH mRNA after induction therapy (40%) (p=0.018) and at the completion of treatment (33%) (p=0.003) were significantly worse than the survival of TH-negative patients (86 and 87%, respectively). In multivariate analysis, MYCN status and TH expression in PB at the end of treatment remained significant prognostic factors. Our results show that patients with advanced neuroblastoma who have PB positive for TH at the end of treatment seem to have a worse prognosis compared with patients with undetectable TH. These results suggest the usefulness of MDD monitoring in neuroblastoma.


Assuntos
Células Neoplásicas Circulantes/metabolismo , Neuroblastoma/diagnóstico , Neuroblastoma/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Tirosina 3-Mono-Oxigenase/sangue , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Microcirculação , Modelos Estatísticos , Análise Multivariada , Neuroblastoma/sangue , Prognóstico , RNA Mensageiro/metabolismo , Recidiva , Sensibilidade e Especificidade , Temperatura Ambiente , Fatores de Tempo , Resultado do Tratamento
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