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1.
Nature ; 486(7403): 405-9, 2012 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-22722202

RESUMO

Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Mutação/genética , Translocação Genética/genética , Algoritmos , Neoplasias da Mama/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/genética , Análise Mutacional de DNA , Exoma/genética , Feminino , Fusão Gênica/genética , Humanos , Proteínas de Membrana/genética , México , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vietnã
2.
Blood ; 125(20): e14-22, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25827832

RESUMO

Immunodeficiency dramatically increases susceptibility to cancer as a result of reduced immune surveillance and enhanced opportunities for virus-mediated oncogenesis. Although AIDS-related lymphomas (ARLs) are frequently associated with known oncogenic viruses, many cases contain no known transforming virus. To discover novel transforming viruses, we profiled a set of ARL samples using whole transcriptome sequencing. We determined that Epstein-Barr virus (EBV) was the only virus detected in the tumor samples of this cohort, suggesting that if unidentified pathogens exist in this disease, they are present in <10% of cases or undetectable by our methods. To evaluate the role of EBV in ARL pathogenesis, we analyzed viral gene expression and found highly heterogeneous patterns of viral transcription across samples. We also found significant heterogeneity of viral antigen expression across a large cohort, with many patient samples presenting with restricted type I viral latency, indicating that EBV latency proteins are under increased immunosurveillance in the post-combined antiretroviral therapies era. Furthermore, EBV infection of lymphoma cells in HIV-positive individuals was associated with a distinct host gene expression program. These findings provide insight into the joint host-virus regulatory network of primary ARL tumor samples and expand our understanding of virus-associated oncogenesis. Our findings may also have therapeutic implications, as treatment may be personalized to target specific viral and virus-associated host processes that are only present in a subset of patients.


Assuntos
Transformação Celular Viral , Linfoma Relacionado a AIDS/etiologia , Vírus Oncogênicos , Infecções Tumorais por Vírus/complicações , Análise por Conglomerados , Estudos de Coortes , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Regulação Viral da Expressão Gênica , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Linfoma Relacionado a AIDS/patologia , Vírus Oncogênicos/genética , Vírus Oncogênicos/imunologia
3.
Proc Natl Acad Sci U S A ; 111(43): 15544-9, 2014 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-25313082

RESUMO

Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.


Assuntos
Genoma Humano/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/virologia , Interações Hospedeiro-Patógeno/genética , Papillomaviridae/fisiologia , Sequência de Bases , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos , Humanos , Dados de Sequência Molecular , Integração Viral/genética
4.
N Engl J Med ; 369(6): 517-28, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-23924002

RESUMO

BACKGROUND: Immunosuppression is associated with a variety of idiopathic clinical syndromes that may have infectious causes. It has been hypothesized that the cord colitis syndrome, a complication of umbilical-cord hematopoietic stem-cell transplantation, is infectious in origin. METHODS: We performed shotgun DNA sequencing on four archived, paraffin-embedded endoscopic colon-biopsy specimens obtained from two patients with cord colitis. Computational subtraction of human and known microbial sequences and assembly of residual sequences into a bacterial draft genome were performed. We used polymerase-chain-reaction (PCR) assays and fluorescence in situ hybridization to determine whether the corresponding bacterium was present in additional patients and controls. RESULTS: DNA sequencing of the biopsy specimens revealed more than 2.5 million sequencing reads that did not match known organisms. These sequences were computationally assembled into a 7.65-Mb draft genome showing a high degree of homology with genomes of bacteria in the bradyrhizobium genus. The corresponding newly discovered bacterium was provisionally named Bradyrhizobium enterica. PCR identified B. enterica nucleotide sequences in biopsy specimens from all three additional patients with cord colitis whose samples were tested, whereas B. enterica sequences were absent in samples obtained from healthy controls and patients with colon cancer or graft-versus-host disease. CONCLUSIONS: We assembled a novel bacterial draft genome from the direct sequencing of tissue specimens from patients with cord colitis. Association of these sequences with cord colitis suggests that B. enterica may be an opportunistic human pathogen. (Funded by the National Cancer Institute and others.)


Assuntos
Bradyrhizobium/genética , Colite/microbiologia , Colo/microbiologia , Sangue Fetal , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções Oportunistas/microbiologia , Biópsia , Bradyrhizobium/classificação , Bradyrhizobium/isolamento & purificação , Colite/imunologia , Neoplasias do Colo/microbiologia , DNA Bacteriano/análise , Diarreia/microbiologia , Feminino , Genoma Bacteriano , Doença Enxerto-Hospedeiro/microbiologia , Humanos , Hospedeiro Imunocomprometido , Masculino , Inclusão em Parafina , Filogenia , Reação em Cadeia da Polimerase , Análise de Sequência de DNA
5.
J Virol ; 89(1): 857-62, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25320321

RESUMO

Malawi polyomavirus (MWPyV) is a recently identified human polyomavirus. Serology for MWPyV VP1 indicates that infection frequently occurs in childhood and reaches a prevalence of 75% in adults. The MWPyV small T antigen (ST) binds protein phosphatase 2A (PP2A), and the large T antigen (LT) binds pRb, p107, p130, and p53. However, the MWPyV LT was less stable than the simian virus 40 (SV40) LT and was unable to promote the growth of normal cells. This report confirms that MWPyV is a widespread human virus expressing T antigens with low transforming potential.


Assuntos
Antígenos Virais de Tumores/metabolismo , Interações Hospedeiro-Patógeno , Infecções por Polyomavirus/epidemiologia , Polyomavirus/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , DNA Viral/química , DNA Viral/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Infecções por Polyomavirus/virologia , Ligação Proteica , Análise de Sequência de DNA , Estudos Soroepidemiológicos , Adulto Jovem
6.
Genome Res ; 22(2): 292-8, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22009990

RESUMO

The tumor microenvironment of colorectal carcinoma is a complex community of genomically altered cancer cells, nonneoplastic cells, and a diverse collection of microorganisms. Each of these components may contribute to carcinogenesis; however, the role of the microbiota is the least well understood. We have characterized the composition of the microbiota in colorectal carcinoma using whole genome sequences from nine tumor/normal pairs. Fusobacterium sequences were enriched in carcinomas, confirmed by quantitative PCR and 16S rDNA sequence analysis of 95 carcinoma/normal DNA pairs, while the Bacteroidetes and Firmicutes phyla were depleted in tumors. Fusobacteria were also visualized within colorectal tumors using FISH. These findings reveal alterations in the colorectal cancer microbiota; however, the precise role of Fusobacteria in colorectal carcinoma pathogenesis requires further investigation.


Assuntos
Neoplasias Colorretais/microbiologia , Fusobacterium/genética , Genoma Bacteriano , Fusobacterium/classificação , Fusobacterium/patogenicidade , Humanos , Intestino Grosso/microbiologia , Metagenoma/genética , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
7.
Proc Natl Acad Sci U S A ; 109(10): 3879-84, 2012 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-22343534

RESUMO

To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase-mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS, BRAF, and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease.


Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Mutação , Motivos de Aminoácidos , Análise por Conglomerados , Análise Mutacional de DNA , Exoma , Éxons , Humanos , Modelos Genéticos , Reação em Cadeia da Polimerase/métodos , Análise de Sequência de DNA , Translocação Genética
8.
Hum Mol Genet ; 18(24): 4843-52, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19783548

RESUMO

Protein cleavage is a common feature in human neurodegenerative disease. Ataxin-3 protein with an expanded polyglutamine (polyQ) repeat causes spinocerebellar ataxia type-3 (SCA3), also called Machado-Joseph disease, and is cleaved in mammalian cells, transgenic mice and SCA3 patient brain tissue. However, the pathological significance of Ataxin-3 cleavage has not been carefully examined. To gain insight into the significance of Ataxin-3 cleavage, we developed a Drosophila SL2 cell-based model as well as transgenic fly models. Our data indicate that Ataxin-3 protein cleavage is conserved in the fly and may be caspase-dependent as reported previously. Importantly, comparison of flies expressing either wild-type or caspase-site mutant proteins indicates that Ataxin-3 cleavage enhances neuronal loss in vivo. This genetic in vivo confirmation of the pathological role of Ataxin-3 cleavage indicates that therapies targeting Ataxin-3 cleavage might slow disease progression in SCA3 patients.


Assuntos
Doença de Machado-Joseph/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Animais Geneticamente Modificados , Ataxina-3 , Inibidores de Caspase , Caspases/metabolismo , Linhagem Celular , Inibidores de Cisteína Proteinase/farmacologia , Modelos Animais de Doenças , Drosophila melanogaster/genética , Humanos , Doença de Machado-Joseph/patologia , Camundongos , Mutagênese Sítio-Dirigida , Proteínas do Tecido Nervoso/genética , Neurônios/patologia , Proteínas Nucleares/genética , Proteínas Repressoras/genética
9.
Virol J ; 7: 309, 2010 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-21067578

RESUMO

BACKGROUND: Cardiomyopathy syndrome (CMS) is a severe disease affecting large farmed Atlantic salmon. Mortality often appears without prior clinical signs, typically shortly prior to slaughter. We recently reported the finding and the complete genomic sequence of a novel piscine reovirus (PRV), which is associated with another cardiac disease in Atlantic salmon; heart and skeletal muscle inflammation (HSMI). In the present work we have studied whether PRV or other infectious agents may be involved in the etiology of CMS. RESULTS: Using high throughput sequencing on heart samples from natural outbreaks of CMS and from fish experimentally challenged with material from fish diagnosed with CMS a high number of sequence reads identical to the PRV genome were identified. In addition, a sequence contig from a novel totivirus could also be constructed. Using RT-qPCR, levels of PRV in tissue samples were quantified and the totivirus was detected in all samples tested from CMS fish but not in controls. In situ hybridization supported this pattern indicating a possible association between CMS and the novel piscine totivirus. CONCLUSIONS: Although causality for CMS in Atlantic salmon could not be proven for either of the two viruses, our results are compatible with a hypothesis where, in the experimental challenge studied, PRV behaves as an opportunist whereas the totivirus might be more directly linked with the development of CMS.


Assuntos
Cardiomiopatias/veterinária , Doenças dos Peixes/virologia , Infecções por Reoviridae/veterinária , Reoviridae/isolamento & purificação , Salmo salar/virologia , Totivirus/isolamento & purificação , Animais , Cardiomiopatias/virologia , Coração/virologia , Histocitoquímica , Hibridização In Situ , Microscopia , Dados de Sequência Molecular , Miocárdio/patologia , RNA Viral/genética , Reoviridae/classificação , Reoviridae/genética , Infecções por Reoviridae/virologia , Análise de Sequência de DNA , Totivirus/classificação , Totivirus/genética
10.
Nat Commun ; 7: 12609, 2016 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-27576846

RESUMO

In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients. Utilizing liquid biopsies, here we demonstrate that TP53 mutations appear in circulating cell-free DNA obtained from patients with de-differentiated liposarcoma being treated with an inhibitor of the HDM2-p53 interaction (SAR405838). TP53 mutation burden increases over time and correlates with change in tumour size, likely representing selection of TP53 mutant clones resistant to HDM2 inhibition. These results provide the first clinical demonstration of the emergence of TP53 mutations in response to an HDM2 antagonist and have significant implications for the clinical development of this class of molecules.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Indóis/farmacologia , Lipossarcoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Compostos de Espiro/farmacologia , Proteína Supressora de Tumor p53/genética , Adulto , Antineoplásicos/uso terapêutico , Biópsia , Diferenciação Celular , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/isolamento & purificação , Análise Mutacional de DNA , Humanos , Indóis/uso terapêutico , Lipossarcoma/sangue , Lipossarcoma/genética , Lipossarcoma/patologia , Mutação , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Critérios de Avaliação de Resposta em Tumores Sólidos , Compostos de Espiro/uso terapêutico , Fatores de Tempo , Proteína Supressora de Tumor p53/metabolismo
11.
Cell Mol Gastroenterol Hepatol ; 2(5): 563-566.e5, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28174737

RESUMO

BACKGROUND & AIMS: Microbial dysbiosis and aberrant host-microbe interactions in the gut are believed to contribute to the development and progression of Crohn's disease (CD). Microbiome studies in CD typically have focused on microbiota in feces or superficial mucosal layers of the colon because accessing DNA from deeper layers of the bowel is challenging. In this study, we analyzed the deep tissue microbiome in patients who underwent surgical resection of the small intestine. METHODS: Paraffin blocks were obtained from 12 CD patients undergoing ileocecal resection, and healthy ileum samples (inflammatory bowel disease-free controls) were obtained from 12 patients undergoing surgery for right-sided colon cancer. Diseased and healthy-appearing ileum was identified using microscopy, and paraffin blocks were macrodissected using a core needle to specifically isolate DNA. Illumina Whole Genome Sequencing was used for microbial sequence identification and subsequent taxonomic classification using the PathSeq tool. RESULTS: We observed significant differences between the microbiome of CD samples vs inflammatory bowel disease-free controls, including depletion of Bacteroidetes and Clostridia. Notably, microbial composition at the phyla level did not differ markedly between healthy and diseased areas of CD patients. However, we observed enrichment of potentially pathogenic organisms at the species level. CONCLUSIONS: Our study showed dysbiosis within deeper layers of the ileum of CD patients, specifically enrichment of enterotoxigenic Staphylococcus aureus and an environmental Mycobacterium species not described previously. Future studies with larger cohort sizes are warranted to confirm these findings. Studies would benefit from effective microbial DNA extraction methods from paraffin sections and host nucleic acid depletion approaches to increase microbial read coverage.

12.
Nat Commun ; 6: 6822, 2015 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-25879913

RESUMO

Artifacts introduced in whole-genome amplification (WGA) make it difficult to derive accurate genomic information from single-cell genomes and require different analytical strategies from bulk genome analysis. Here, we describe statistical methods to quantitatively assess the amplification bias resulting from whole-genome amplification of single-cell genomic DNA. Analysis of single-cell DNA libraries generated by different technologies revealed universal features of the genome coverage bias predominantly generated at the amplicon level (1-10 kb). The magnitude of coverage bias can be accurately calibrated from low-pass sequencing (∼0.1 × ) to predict the depth-of-coverage yield of single-cell DNA libraries sequenced at arbitrary depths. We further provide a benchmark comparison of single-cell libraries generated by multi-strand displacement amplification (MDA) and multiple annealing and looping-based amplification cycles (MALBAC). Finally, we develop statistical models to calibrate allelic bias in single-cell whole-genome amplification and demonstrate a census-based strategy for efficient and accurate variant detection from low-input biopsy samples.


Assuntos
Alelos , Genoma Humano , Genômica/métodos , Análise de Célula Única/métodos , Estatística como Assunto , Viés , Calibragem , Linhagem Celular , Biblioteca Gênica , Humanos , Técnicas de Amplificação de Ácido Nucleico , Reação em Cadeia da Polimerase , Análise de Sequência de DNA
13.
Cancer Discov ; 4(8): 956-71, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24893890

RESUMO

UNLABELLED: Glioblastomas (GBM) with EGFR amplification represent approximately 50% of newly diagnosed cases, and recent studies have revealed frequent coexistence of multiple EGFR aberrations within the same tumor, which has implications for mutation cooperation and treatment resistance. However, bulk tumor sequencing studies cannot resolve the patterns of how the multiple EGFR aberrations coexist with other mutations within single tumor cells. Here, we applied a population-based single-cell whole-genome sequencing methodology to characterize genomic heterogeneity in EGFR-amplified glioblastomas. Our analysis effectively identified clonal events, including a novel translocation of a super enhancer to the TERT promoter, as well as subclonal LOH and multiple EGFR mutational variants within tumors. Correlating the EGFR mutations onto the cellular hierarchy revealed that EGFR truncation variants (EGFRvII and EGFR carboxyl-terminal deletions) identified in the bulk tumor segregate into nonoverlapping subclonal populations. In vitro and in vivo functional studies show that EGFRvII is oncogenic and sensitive to EGFR inhibitors currently in clinical trials. Thus, the association between diverse activating mutations in EGFR and other subclonal mutations within a single tumor supports an intrinsic mechanism for proliferative and clonal diversification with broad implications in resistance to treatment. SIGNIFICANCE: We developed a novel single-cell sequencing methodology capable of identifying unique, nonoverlapping subclonal alterations from archived frozen clinical specimens. Using GBM as an example, we validated our method to successfully define tumor cell subpopulations containing distinct genetic and treatment resistance profiles and potentially mutually cooperative combinations of alterations in EGFR and other genes.


Assuntos
Receptores ErbB/genética , Glioblastoma/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Célula Única/métodos , Núcleo Celular/genética , Genoma Humano , Glioblastoma/patologia , Humanos , Perda de Heterozigosidade , Mutação
14.
Cancer Res ; 73(16): 5195-205, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23786770

RESUMO

A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, each of which are observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small-molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. In addition, we report a patient with an FGFR2-mutated oral SCC who responded to the multitargeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SCC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Mutação , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Dimerização , Humanos , Indazóis , Interleucina-3/genética , Interleucina-3/metabolismo , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Células NIH 3T3 , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Sulfonamidas/farmacologia
15.
Genetics ; 187(1): 61-71, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21041558

RESUMO

Trinucleotide repeat instability underlies >20 human hereditary disorders. These diseases include many neurological and neurodegenerative situations, such as those caused by pathogenic polyglutamine (polyQ) domains encoded by expanded CAG repeats. Although mechanisms of instability have been intensely studied, our knowledge remains limited in part due to the lack of unbiased genome-wide screens in multicellular eukaryotes. Drosophila melanogaster displays triplet repeat instability with features that recapitulate repeat instability seen in patients with disease. Here we report an enhanced fly model with substantial instability based on a noncoding 270 CAG (UAS-CAG(270)) repeat construct under control of a germline-specific promoter. We find that expression of pathogenic polyQ protein modulates repeat instability of CAG(270) in trans, indicating that pathogenic-length polyQ proteins may globally modulate repeat instability in the genome in vivo. We further performed an unbiased genetic screen for novel modifiers of instability. These studies indicate that different aspects of repeat instability are under independent genetic control, and identify CG15262, a protein with a NOT2/3/5 conserved domain, as a modifier of CAG repeat instability in vivo.


Assuntos
Drosophila melanogaster/genética , Instabilidade Genômica/genética , Repetições de Trinucleotídeos/genética , Animais , Animais Geneticamente Modificados , Sequência de Bases , Drosophila melanogaster/metabolismo , Feminino , Regulação da Expressão Gênica , Proteínas de Homeodomínio/química , Humanos , Proteínas de Insetos/química , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Masculino , Peptídeos/genética , Estrutura Terciária de Proteína , Sequências Reguladoras de Ácido Nucleico/genética , Homologia de Sequência de Aminoácidos
16.
Science ; 315(5820): 1857-9, 2007 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-17332375

RESUMO

Although expansion of trinucleotide repeats accounts for over 30 human diseases, mechanisms of repeat instability remain poorly understood. We show that a Drosophila model for the CAG/polyglutamine (polyQ) disease spinocerebellar ataxia type 3 recapitulates key features of human CAG-repeat instability, including large repeat changes and strong expansion bias. Instability is dramatically enhanced by transcription and modulated by nuclear excision repair and a regulator of DNA repair adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB)-binding protein-a histone acetyltransferase (HAT) whose decreased activity contributes to polyQ disease. Pharmacological treatment to normalize acetylation suppressed instability. Thus, toxic consequences of pathogenic polyQ protein may include enhancing repeat instability.


Assuntos
Proteína de Ligação a CREB/metabolismo , Drosophila melanogaster/genética , Instabilidade Genômica , Doença de Machado-Joseph/genética , Transcrição Gênica , Expansão das Repetições de Trinucleotídeos , Repetições de Trinucleotídeos , Alelos , Animais , Animais Geneticamente Modificados , Antecipação Genética , Proteína de Ligação a CREB/genética , Reparo do DNA , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Feminino , Síndrome do Cromossomo X Frágil/genética , Inibidores de Histona Desacetilases , Humanos , Doença de Huntington/genética , Ácidos Hidroxâmicos/farmacologia , Masculino , Modelos Animais , Peptídeos/química , Transgenes
18.
Gastroenterology ; 123(1): 345-51, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12105862

RESUMO

BACKGROUND & AIMS: Liver development, regeneration, and oncogenesis involve signaling events mediated by a number of proteins, such as ras and the related small guanosine triphosphatases. Many of these signaling proteins carry unique CAAX motifs, which are processed by prenylcysteine carboxylmethyltransferase (PCCMT), among several other enzymes. We investigated the function of Pccmt during mouse liver development to better understand the embryonic lethality of the null mutation. METHODS: Generation of Pccmt-null mice by embryonic stem cell technology, molecular and histologic analysis of Pccmt-null embryos, and foregut endoderm cultures. RESULTS: Pccmt-null embryos die in utero with severe anemia and extensive apoptosis at embryonic day 10.5. We show that deletion of Pccmt leads to a dramatic delay in albumin induction, an early and definitive marker for hepatocyte development. In tissue explant cultures supplemented with fibroblast growth factor (FGF), albumin induction remained impaired. We found that hepatocyte precursors in Pccmt-null embryos failed to invade the septum transversum, resulting in liver agenesis. CONCLUSIONS: PCCMT is essential for several stages of hepatic induction, consistent with its role in modifying proteins required to transduce signals, such as FGF, that have been shown to promote liver specification and early growth.


Assuntos
Fígado/embriologia , Proteínas Metiltransferases/fisiologia , Anemia/complicações , Anemia/embriologia , Animais , Apoptose , Senescência Celular/fisiologia , Técnicas de Cultura , Embrião de Mamíferos/fisiologia , Desenvolvimento Embrionário e Fetal/fisiologia , Feminino , Morte Fetal/etiologia , Fatores de Crescimento de Fibroblastos/farmacologia , Hepatócitos/fisiologia , Fígado/anormalidades , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout/genética , Proteínas Metiltransferases/genética , Albumina Sérica/metabolismo , Células-Tronco/fisiologia
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