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1.
Genes Dev ; 29(24): 2547-62, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26637281

RESUMO

Alterations of chromatin modifiers are frequent in cancer, but their functional consequences often remain unclear. Focusing on the Polycomb protein EZH2 that deposits the H3K27me3 (trimethylation of Lys27 of histone H3) mark, we showed that its high expression in solid tumors is a consequence, not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process malfunctions in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes actually indicate poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes that are consequences of EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2's contribution to solid tumors with important therapeutic implications.


Assuntos
Neoplasias da Mama/enzimologia , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica/genética , Complexo Repressor Polycomb 2/metabolismo , Animais , Animais Geneticamente Modificados , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Histonas/metabolismo , Homeostase/genética , Humanos , Masculino , Complexo Repressor Polycomb 2/genética , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética
2.
Bioinformatics ; 26(15): 1895-6, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20639544

RESUMO

SUMMARY: We present SVDetect, a program designed to identify genomic structural variations from paired-end and mate-pair next-generation sequencing data produced by the Illumina GA and ABI SOLiD platforms. Applying both sliding-window and clustering strategies, we use anomalously mapped read pairs provided by current short read aligners to localize genomic rearrangements and classify them according to their type, e.g. large insertions-deletions, inversions, duplications and balanced or unbalanced inter-chromosomal translocations. SVDetect outputs predicted structural variants in various file formats for appropriate graphical visualization. AVAILABILITY: Source code and sample data are available at http://svdetect.sourceforge.net/


Assuntos
Genoma/genética , Variação Estrutural do Genoma , Genômica/métodos , Software
3.
PLoS Genet ; 3(10): 1907-21, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17937502

RESUMO

Drosophila provides a powerful system for defining the complex genetic programs that drive organogenesis. Under control of the steroid hormone ecdysone, the adult heart in Drosophila forms during metamorphosis by a remodelling of the larval cardiac organ. Here, we evaluated the extent to which transcriptional signatures revealed by genomic approaches can provide new insights into the molecular pathways that underlie heart organogenesis. Whole-genome expression profiling at eight successive time-points covering adult heart formation revealed a highly dynamic temporal map of gene expression through 13 transcript clusters with distinct expression kinetics. A functional atlas of the transcriptome profile strikingly points to the genomic transcriptional response of the ecdysone cascade, and a sharp regulation of key components belonging to a few evolutionarily conserved signalling pathways. A reverse genetic analysis provided evidence that these specific signalling pathways are involved in discrete steps of adult heart formation. In particular, the Wnt signalling pathway is shown to participate in inflow tract and cardiomyocyte differentiation, while activation of the PDGF-VEGF pathway is required for cardiac valve formation. Thus, a detailed temporal map of gene expression can reveal signalling pathways responsible for specific developmental programs and provides here substantial grasp into heart formation.


Assuntos
Perfilação da Expressão Gênica , Coração/fisiologia , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Ecdisona/metabolismo , Regulação da Expressão Gênica , Genoma , Cinética , Miocárdio/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Transcrição Gênica , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Commun Biol ; 3(1): 367, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647357

RESUMO

Patient-derived xenografts (PDX) have emerged as an important translational research tool for understanding tumor biology and enabling drug efficacy testing. They are established by transfer of patient tumor into immune compromised mice with the intent of using them as Avatars; operating under the assumption that they closely resemble patient tumors. In this study, we established 27 PDX from 100 resected gastric cancers and studied their fidelity in histological and molecular subtypes. We show that the established PDX preserved histology and molecular subtypes of parental tumors. However, in depth investigation of the entire cohort revealed that not all histological and molecular subtypes are established. Also, for the established PDX models, genetic changes are selected at early passages and rare subclones can emerge in PDX. This study highlights the importance of considering the molecular and evolutionary characteristics of PDX for a proper use of such models, particularly for Avatar trials.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/classificação , Neoplasias Gástricas/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Eur J Hum Genet ; 22(4): 535-41, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23942203

RESUMO

To meet challenges in terms of throughput and turnaround time, many diagnostic laboratories are shifting from Sanger sequencing to higher throughput next-generation sequencing (NGS) platforms. Bearing in mind that the performance and quality criteria expected from NGS in diagnostic or research settings are strikingly different, we have developed an Ion Torrent's PGM-based routine diagnostic procedure for BRCA1/2 sequencing. The procedure was first tested on a training set of 62 control samples, and then blindly validated on 77 samples in parallel with our routine technique. The training set was composed of difficult cases, for example, insertions and/or deletions of various sizes, large-scale rearrangements and, obviously, mutations occurring in homopolymer regions. We also compared two bioinformatic solutions in this diagnostic context, an in-house academic pipeline and the commercially available NextGene software (Softgenetics). NextGene analysis provided higher sensitivity, as four previously undetected single-nucleotide variations were found. Regarding specificity, an average of 1.5 confirmatory Sanger sequencings per patient was needed for complete BRCA1/2 screening. Large-scale rearrangements were identified by two distinct analyses, that is, bioinformatics and fragment analysis with electrophoresis profile comparison. Turnaround time was enhanced, as a series of 30 patients were sequenced by one technician, making the results available for the clinician in 10 working days following blood sampling. BRCA1/2 genes are a good model, representative of the difficulties commonly encountered in diagnostic settings, which is why we believe our findings are of interest for the whole community, and the pipeline described can be adapted by any user of PGM for diagnostic purposes.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Biologia Computacional , Feminino , Rearranjo Gênico , Testes Genéticos , Humanos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Sensibilidade e Especificidade , Análise de Sequência de DNA , Deleção de Sequência , Software
7.
Front Genet ; 5: 152, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24910641

RESUMO

Precision medicine (PM) requires the delivery of individually adapted medical care based on the genetic characteristics of each patient and his/her tumor. The last decade witnessed the development of high-throughput technologies such as microarrays and next-generation sequencing which paved the way to PM in the field of oncology. While the cost of these technologies decreases, we are facing an exponential increase in the amount of data produced. Our ability to use this information in daily practice relies strongly on the availability of an efficient bioinformatics system that assists in the translation of knowledge from the bench towards molecular targeting and diagnosis. Clinical trials and routine diagnoses constitute different approaches, both requiring a strong bioinformatics environment capable of (i) warranting the integration and the traceability of data, (ii) ensuring the correct processing and analyses of genomic data, and (iii) applying well-defined and reproducible procedures for workflow management and decision-making. To address the issues, a seamless information system was developed at Institut Curie which facilitates the data integration and tracks in real-time the processing of individual samples. Moreover, computational pipelines were developed to identify reliably genomic alterations and mutations from the molecular profiles of each patient. After a rigorous quality control, a meaningful report is delivered to the clinicians and biologists for the therapeutic decision. The complete bioinformatics environment and the key points of its implementation are presented in the context of the SHIVA clinical trial, a multicentric randomized phase II trial comparing targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer. The numerous challenges faced in practice during the setting up and the conduct of this trial are discussed as an illustration of PM application.

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