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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 299: 122840, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37196554

RESUMO

In this work, through the orthogonal design of two fluorophores and two recognition groups, a series of fluorescent probes were developed from the flavone derivatives for hydrogen sulfide (H2S). The probe FlaN-DN stood out from the primarily screening on the selectivity and response intensities. It could respond to H2S with both the chromogenic and fluorescent signals. Among the recent reported probes for the H2S detection, FlaN-DN indicated the most highlighted advantages including the rapid response (within 200 s) and the high response multiplication (over 100 folds). FlaN-DN was sensitive to the pH condition, thus could be applied to distinguish the cancer micro-environment. Moreover, FlaN-DN suggested practical capabilities including a wide linear range (0-400 µM), a relatively high sensitivity (limit of detection 0.13 µM), and high selectivity towards H2S. As a low cytotoxic probe, FlaN-DN achieved the imaging in living HeLa cells. FlaN-DN could detect the endogenous generation H2S and visualize the dose-dependent responses to the exogenous H2S level. This work provided a typical case of natural-sourced derivatives as functional implements, which might inspire the future investigations.


Assuntos
Flavonas , Sulfeto de Hidrogênio , Humanos , Células HeLa , Corantes Fluorescentes , Microscopia de Fluorescência/métodos
2.
Cell Discov ; 7(1): 98, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34697290

RESUMO

The amino acid response (AAR) and unfolded protein response (UPR) pathways converge on eIF2α phosphorylation, which is catalyzed by Gcn2 and Perk, respectively, under different stresses. This close interconnection makes it difficult to specify different functions of AAR and UPR. Here, we generated a zebrafish model in which loss of threonyl-tRNA synthetase (Tars) induces angiogenesis dependent on Tars aminoacylation activity. Comparative transcriptome analysis of the tars-mutant and wild-type embryos with/without Gcn2- or Perk-inhibition reveals that only Gcn2-mediated AAR is activated in the tars-mutants, whereas Perk functions predominantly in normal development. Mechanistic analysis shows that, while a considerable amount of eIF2α is normally phosphorylated by Perk, the loss of Tars causes an accumulation of uncharged tRNAThr, which in turn activates Gcn2, leading to phosphorylation of an extra amount of eIF2α. The partial switchover of kinases for eIF2α largely overwhelms the functions of Perk in normal development. Interestingly, although inhibition of Gcn2 and Perk in this stress condition both can reduce the eIF2α phosphorylation levels, their functional consequences in the regulation of target genes and in the rescue of the angiogenic phenotypes are dramatically different. Indeed, genetic and pharmacological manipulations of these pathways validate that the Gcn2-mediated AAR, but not the Perk-mediated UPR, is required for tars-deficiency induced angiogenesis. Thus, the interconnected AAR and UPR pathways differentially regulate angiogenesis through selective functions and mutual competitions, reflecting the specificity and efficiency of multiple stress response pathways that evolve integrally to enable an organism to sense/respond precisely to various types of stresses.

3.
Zhongguo Zhong Yao Za Zhi ; 46(17): 4446-4455, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34581049

RESUMO

Twenty batches of Aurantii Fructus Immaturus(AFI) were collected, with their peel and pulp taken as research objects. Ultra-high performance liquid chromatography(UPLC) fingerprints of peel and pulp of AFI were established with 17 common peaks in peel and 10 in pulp. Six kinds of flavonoids were identified, i.e., narirutin, naringin, rhoifolin, hesperidin, neohesperidin and nobiletin. The Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine was employed for similarity analysis, which showed that the chromatographic peaks of peel and pulp were basically similar to their respective reference fingerprints, with all similarities greater than 0.90. The similarity between peel and pulp of the same batch of AFI ranged from 0.850 to 0.983. Cluster analysis(CA), principal component analysis(PCA), and orthogonal partial least squares discriminant analysis(OPLS-DA) were conducted on the common peaks of peel and pulp of AFI with SPSS 17.0 and SIMCA 14.1. Combined with the reference fingerprints, these analyses revealed 12 differential components regarding peel and pulp. Further, the content of the 6 flavonoids and synephrine was determined. The proposed method integrating UPLC fingerprint and multicomponent quantitative analysis is applicable to the quality evaluation of AFI. The results provide a certain basis for the scientific connotation about the appearance characteristic of AFI.


Assuntos
Citrus , Medicamentos de Ervas Chinesas , Cromatografia Líquida de Alta Pressão , Sinefrina
4.
World J Gastrointest Surg ; 13(12): 1567-1583, 2021 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-35070064

RESUMO

Mucinous adenocarcinoma (MAC) is a unique clinicopathological subtype of colorectal cancer, which is characterized by extracellular mucinous components that comprise at least 50% of the tumor tissue. The clinical characteristics, molecular features, response to chemo-/radiotherapy, and prognosis of MAC are different from that of non-MAC (NMAC). MAC is more common in the proximal colon, with larger volume, higher T-stage, a higher proportion of positive lymph nodes, poorer tumor differentiation, and a higher proportion of peritoneal implants compared to NMAC. Although biopsy is the main diagnostic method for MAC, magnetic resonance imaging is superior in accuracy, especially for rectal carcinoma. The aberrant expression of mucins, including MUC1, MUC2 and MUC5AC, is a notable feature of MAC, which may be related to tumor invasion, metastasis, inhibition of apoptosis, and chemo-/radiotherapy resistance. The genetic origin of MAC is mainly related to BRAF mutation, microsatellite instability, and the CpG island methylator phenotype pathway. In addition, the poor prognosis of rectal MAC has been confirmed by various studies, and that of colonic MAC is still controversial. In this review, we summarize the epidemiology, clinicopathological characteristics, molecular features, methods of diagnosis, and treatments of MAC in order to provide references for further fundamental and clinical research.

5.
J Clin Endocrinol Metab ; 102(2): 652-660, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27809695

RESUMO

Context: Graves disease (GD) is a common autoimmune disease triggered by genetic predisposition and environmental factors. However, the mechanisms of interaction between genetic and environmental factors contributing to the development of GD remain unknown. Objective: We aimed to identify GD susceptibility variants and genes on Xq21.1 locus and interpret the contribution of interaction between genetic predisposition on Xq21.1 and environmental factors to GD. Design: We performed refining study on Xq21.1 in a 2-stage study and carried out expression quantitative trait locus analysis of the best association signal with GD. Setting and Participants: A total of 4316 GD patients and 4374 sex-matched controls were collected from the Chinese Han population by cooperation with multiple hospitals. Results: We identified that rs3827440 or its linkage single nucleotide polymorphisms (SNPs) were probably the causal variant in the Xq21.1 locus, with the most substantial association with GD in our combined cohorts (P = 2.45 × 10-15). The genotypes of rs3827440 were correlated with the expression of ITM2A in monocytes and peripheral blood mononuclear cells (PBMCs) from healthy volunteers. Notably, the expression of ITM2A in monocytes after lipopolysaccharide (LPS) and interferon-γ (INF-γ) stimulation showed substantial difference among the volunteers that carried different genotypes of rs3827440 (P = 9.40 × 10-7 and P = 1.26 × 10-5 for 24 hours' LPS and INF-γ stimulation, respectively). Moreover, ITM2A expression was significantly decreased in PBMCs from untreated GD patients than that from controls. Conclusion: The results suggest that ITM2A might be a susceptibility gene for GD in the Xq21.1 locus, and environmental factors, such as viral and bacterial infections, probably contribute to GD pathogenesis by interacting with the risk SNP rs3827440 mediating the regulation of ITM2A expression.


Assuntos
Infecções Bacterianas/complicações , Interação Gene-Ambiente , Doença de Graves/etiologia , Doença de Graves/genética , Leucócitos Mononucleares/metabolismo , Proteínas de Membrana/genética , Viroses/complicações , China , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença de Graves/sangue , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
6.
EBioMedicine ; 2(6): 563-71, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26285909

RESUMO

BACKGROUND: Acute promyelocytic leukemia (APL) is a model for synergistic target cancer therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which yields a very high 5-year overall survival (OS) rate of 85 to 90%. Nevertheless, about 15% of APL patients still get early death or relapse. We performed this study to address the possible impact of additional gene mutations on the outcome of APL. METHODS: We included a consecutive series of 266 cases as training group, and then validated the results in a testing group of 269 patients to investigate the potential prognostic gene mutations, including FLT3-ITD or -TKD, N-RAS, C-KIT, NPM1, CEPBA, WT1, ASXL1, DNMT3A, MLL (fusions and PTD), IDH1, IDH2 and TET2. RESULTS: More high-risk patients (50.4%) carried additional mutations, as compared with intermediate- and low-risk ones. The mutations of epigenetic modifier genes were associated with poor prognosis in terms of disease-free survival in both training (HR = 6.761, 95% CI 2.179-20.984; P = 0.001) and validation (HR = 4.026, 95% CI 1.089-14.878; P = 0.037) groups. Sanz risk stratification was associated with CR induction and OS. CONCLUSION: In an era of ATRA/ATO treatment, both molecular markers and clinical parameter based stratification systems should be used as prognostic factors for APL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arsenicais/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Óxidos/uso terapêutico , Tretinoína/uso terapêutico , Adolescente , Adulto , Idoso , Trióxido de Arsênio , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Intervalo Livre de Doença , Epigênese Genética/genética , Feminino , Genes Modificadores/genética , Humanos , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação/genética , Nucleofosmina , Prognóstico , Resultado do Tratamento , Adulto Jovem
7.
Nat Genet ; 47(9): 1061-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26192917

RESUMO

Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56(+) and cytoCD3(+) lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.


Assuntos
RNA Helicases DEAD-box/genética , Exoma , Linfoma de Células T/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Ciclo Celular , Análise Mutacional de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células T/mortalidade , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Prognóstico , Transdução de Sinais , Dissomia Uniparental/genética , Adulto Jovem
8.
Cell Biochem Biophys ; 71(1): 235-41, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25108737

RESUMO

The clinical significance of low-frequency microsatellite instability (MSI-L) in gastric cancer (GC) has not been well established. The aim of this study was to evaluate the clinicopathological features of MSI-L in GC. We investigated microsatellite instability (MSI) in 5 di-nucleotide repeat sequences in 210 unselected GC patients. High-resolution fluorescent microsatellite analysis assay was utilized to detect MSI. Clinicopathological variables were compared among groups with different microsatellite statuses. The overall survival (OS) was analyzed by Kaplan-Meier method. Multivariable analysis was performed to identify prognostic factors and variables correlated with lymph node metastasis. High-frequency microsatellite instability (MSI-H), MSI-L, and microsatellite stable were identified, respectively, in 10.5, 10.0, and 79.5% of unselected GC cases. Tumors with MSI-H were less invasive, and these patients showed a better OS. MSI-L was correlated with more advanced tumor Node Metastasis stage, and more frequent lymph node metastasis. The unfavorable prognosis predicted by MSI-L was ascribed to its correlation with lymphatic invasion. MSI-L characterized by di-nucleotide markers represents a distinct subcategory of GC with aggressive clinicopathological features, which are particularly affiliated to lymphatic system and correlated with a poor prognosis. MSI-L could be beneficial for predicting the clinical outcome of GC.


Assuntos
Repetições de Dinucleotídeos , Genômica , Instabilidade de Microssatélites , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Neoplasias Gástricas/patologia , Análise de Sobrevida
9.
Proc Natl Acad Sci U S A ; 111(23): 8589-94, 2014 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24850867

RESUMO

Myelodysplastic syndrome (MDS) includes a group of diseases characterized by dysplasia of bone marrow myeloid lineages with ineffective hematopoiesis and frequent evolution to acute myeloid leukemia (AML). Whole-genome sequencing was performed in CD34(+) hematopoietic stem/progenitor cells (HSPCs) from eight cases of refractory anemia with excess blasts (RAEB), the high-risk subtype of MDS. The nucleotide substitution patterns were found similar to those reported in AML, and mutations of 96 protein-coding genes were identified. Clonal architecture analysis revealed the presence of subclones in six of eight cases, whereas mutation detection of CD34(+) versus CD34(-) cells revealed heterogeneity of HSPC expansion status. With 39 marker genes belonging to eight functional categories, mutations were analyzed in 196 MDS cases including mostly RAEB (n = 89) and refractory cytopenia with multilineage dysplasia (RCMD) (n = 95). At least one gene mutation was detected in 91.0% of RAEB, contrary to that in RCMD (55.8%), suggesting a higher mutational burden in the former group. Gene abnormality patterns differed between MDS and AML, with mutations of activated signaling molecules and NPM1 being rare, whereas those of spliceosome more common, in MDS. Finally, gene mutation profiles also bore prognostic value in terms of overall survival and progression free survival.


Assuntos
Genoma Humano/genética , Genômica/métodos , Células-Tronco Hematopoéticas/metabolismo , Mutação , Síndromes Mielodisplásicas/genética , Antígenos CD34/metabolismo , Biomarcadores Tumorais/genética , Diferenciação Celular/genética , Proliferação de Células , Evolução Clonal , Feminino , Humanos , Estimativa de Kaplan-Meier , Cariotipagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/diagnóstico , Nucleofosmina , Prognóstico , Análise de Sequência de DNA/métodos
10.
PLoS One ; 9(2): e89302, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24586676

RESUMO

The interrelationship between genetic susceptibility and carcinogenic exposure is important in cancer development. Polymorphisms in detoxification enzymes of the glutathione-S-transferases (GST) family are associated with an increased incidence of lymphoma. Here we investigated the molecular connection of the genetic polymorphism of GSTT1 to the response of lymphocytes to polycyclic aromatic hydrocarbons (PAH). In neoplastic situation, GSTT1 deletions were more frequently observed in lymphoma patients (54.9%) than in normal controls (42.0%, P = 0.009), resulting in an increased risk for lymphoma in individuals with GSTT1-null genotype (Odds ratio = 1.698, 95% confidence interval = 1.145-2.518). GSTT1 gene and protein expression were accordingly decreased in GSTT1-deleting patients, consistent with activated profile of cell cycle regulation genes. Mimicking environmental exposure using long-term repeat culture with low-dose PAH metabolite Hydroquinone, malignant B- and T-lymphocytes presented increased DNA damage, pCHK1/MYC expression and cell proliferation, which were counteracted by ectopic expression of GSTT1. Moreover, GSTT1 expression retarded xenograft tumor formation of Hydroquinone-treated lymphoma cells in nude mice. In non-neoplastic situation, when zebrafish was exposed to PAH Benzo(a)pyrene, molecular silencing of gstt1 enhanced the proliferation of normal lymphocytes and upregulated myca expression. Collectively, these findings suggested that GSTT1 deletion is related to genetic predisposition to lymphoma, particularly interacting with environmental pollutants containing PAH.


Assuntos
Dano ao DNA/efeitos dos fármacos , Glutationa Transferase/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Células T/patologia , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Polimorfismo Genético/genética , Deleção de Sequência/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Proliferação de Células/efeitos dos fármacos , Adutos de DNA , Variações do Número de Cópias de DNA/genética , Dano ao DNA/genética , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Genoma Humano , Genótipo , Humanos , Técnicas Imunoenzimáticas , Hibridização In Situ , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/etiologia , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/etiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
11.
Proc Natl Acad Sci U S A ; 110(9): 3495-500, 2013 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-23382200

RESUMO

The refractoriness of acute promyelocytic leukemia (APL) with t(11;17)(q23;q21) to all-trans retinoic acid (ATRA)-based therapy concerns clinicians and intrigues basic researchers. By using a murine leukemic model carrying both promyelocytic leukemia zinc finger/retinoic acid receptor-α (PLZF/RARα) and RARα/PLZF fusion genes, we discovered that 8-chlorophenylthio adenosine-3', 5'-cyclic monophosphate (8-CPT-cAMP) enhances cellular differentiation and improves gene trans-activation by ATRA in leukemic blasts. Mechanistically, in combination with ATRA, 8-CPT-cAMP activates PKA, causing phosphorylation of PLZF/RARα at Ser765 and resulting in increased dissociation of the silencing mediator for retinoic acid and thyroid hormone receptors/nuclear receptor corepressor from PLZF/RARα. This process results in changes of local chromatin and transcriptional reactivation of the retinoic acid pathway in leukemic cells. Meanwhile, 8-CPT-cAMP also potentiated ATRA-induced degradation of PLZF/RARα through its Ser765 phosphorylation. In vivo treatment of the t(11;17) APL mouse model demonstrated that 8-CPT-cAMP could significantly improve the therapeutic effect of ATRA by targeting a leukemia-initiating cell activity. This combined therapy, which induces enhanced differentiation and oncoprotein degradation, may benefit t(11;17) APL patients.


Assuntos
Diferenciação Celular , AMP Cíclico/análogos & derivados , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteínas de Fusão Oncogênica/metabolismo , Proteólise , Tionucleotídeos/uso terapêutico , Translocação Genética , Tretinoína/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 17/genética , AMP Cíclico/farmacologia , AMP Cíclico/uso terapêutico , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Correpressor 2 de Receptor Nuclear/metabolismo , Fosforilação/efeitos dos fármacos , Fosfosserina/metabolismo , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Tionucleotídeos/farmacologia , Translocação Genética/efeitos dos fármacos , Tretinoína/farmacologia
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 20(1): 12-7, 2012 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-22391156

RESUMO

Abnormalities of chromosome 11 involving mixed lineage leukemia (MLL) on 11q23 are often seen in acute myeloid leukemia (AML)-M5 or AML-M4. The fusion gene of MLL-PTD and MLL plays a critical role in the pathogenesis of these AML. However, rare chromosome abnormalities have been identified in this type of leukemia. To explore whether there were other MLL gene mutations at M4 and M5, in this study all of the MLL exons were sequenced at cDNA level. 25 patients with de novo AML-M4 or M5 with normal karyotypes excluding M4eo and MLL fusion gene or MLL-PTD were selected, the amplification and direct sequencing analysis of full length MLL gene exons were carried out, then the mutations found were verified at genomic DNA level. Furthermore, the point mutations were tested in normal samples and a larger group of AML patients using the platform of Mass Array. The results showed that high-frequency deletion/insertion and point mutations in RD, PHD, TAD and SET domains of MLL were found, while these alterations in normal samples and other subtypes of AML samples were also verified, and without significant difference (P > 0.05). It is concluded that a variety of deletions/insertions in MLL mRNA and point mutations are respectively alternative splicing of MLL gene at transcriptional level and single nucleotide polymorphism. These alternations together constituted genetic polymorphisms of MLL. Although these variations may not play a direct role in the molecular pathogenesis of AML-M4 or M5, their correlations to clinical treatment and prognosis need to be further explored.


Assuntos
Cromossomos Humanos Par 11/genética , Leucemia Monocítica Aguda/genética , Mutação , Processamento Alternativo , Sequência de Bases , Análise Mutacional de DNA , Histona-Lisina N-Metiltransferase , Humanos , Leucemia Mielomonocítica Aguda/genética , Dados de Sequência Molecular , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética
13.
Blood ; 118(20): 5593-603, 2011 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-21881046

RESUMO

To evaluate the prognostic value of genetic mutations for acute myeloid leukemia (AML) patients, we examined the gene status for both fusion products such as AML1 (CBFα)-ETO, CBFß-MYH11, PML-RARα, and MLL rearrangement as a result of chromosomal translocations and mutations in genes including FLT3, C-KIT, N-RAS, NPM1, CEBPA, WT1, ASXL1, DNMT3A, MLL, IDH1, IDH2, and TET2 in 1185 AML patients. Clinical analysis was mainly carried out among 605 cases without recognizable karyotype abnormalities except for 11q23. Of these 605 patients, 452 (74.7%) were found to have at least 1 mutation, and the relationship of gene mutations with clinical outcome was investigated. We revealed a correlation pattern among NPM1, DNMT3A, FLT3, IDH1, IDH2, CEBPA, and TET2 mutations. Multivariate analysis identified DNMT3A and MLL mutations as independent factors predicting inferior overall survival (OS) and event-free survival (EFS), whereas biallelic CEBPA mutations or NPM1 mutations without DNMT3A mutations conferred a better OS and EFS in both the whole group and among younger patients < 60 years of age. The use of molecular markers allowed us to subdivide the series of 605 patients into distinct prognostic groups with potential clinical relevance.


Assuntos
Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica/genética , Testes Genéticos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/genética , DNA Metiltransferase 3A , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Marcadores Genéticos , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Nucleofosmina , Proteínas de Fusão Oncogênica/genética , Valor Preditivo dos Testes , Prognóstico , Adulto Jovem
14.
Nat Genet ; 43(9): 897-901, 2011 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-21841780

RESUMO

Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (P(combined) = 6.85 × 10(-10) for rs9355610) and an intergenic region at 4p14 (P(combined) = 1.08 × 10(-13) for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Doença de Graves/genética , Receptores da Tireotropina/genética , Autoanticorpos/sangue , Feminino , Estudo de Associação Genômica Ampla , Doença de Graves/epidemiologia , Doença de Graves/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Masculino , Dados de Sequência Molecular , Receptores da Tireotropina/imunologia , Risco
15.
Nat Genet ; 43(4): 309-15, 2011 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-21399634

RESUMO

Abnormal epigenetic regulation has been implicated in oncogenesis. We report here the identification of somatic mutations by exome sequencing in acute monocytic leukemia, the M5 subtype of acute myeloid leukemia (AML-M5). We discovered mutations in DNMT3A (encoding DNA methyltransferase 3A) in 23 of 112 (20.5%) cases. The DNMT3A mutants showed reduced enzymatic activity or aberrant affinity to histone H3 in vitro. Notably, there were alterations of DNA methylation patterns and/or gene expression profiles (such as HOXB genes) in samples with DNMT3A mutations as compared with those without such changes. Leukemias with DNMT3A mutations constituted a group of poor prognosis with elderly disease onset and of promonocytic as well as monocytic predominance among AML-M5 individuals. Screening other leukemia subtypes showed Arg882 alterations in 13.6% of acute myelomonocytic leukemia (AML-M4) cases. Our work suggests a contribution of aberrant DNA methyltransferase activity to the pathogenesis of acute monocytic leukemia and provides a useful new biomarker for relevant cases.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Monocítica Aguda/enzimologia , Leucemia Monocítica Aguda/genética , Mutação de Sentido Incorreto , Adulto , Idoso , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência de Bases , Biomarcadores Tumorais/genética , Sequência Conservada , DNA (Citosina-5-)-Metiltransferases/química , Metilação de DNA/genética , DNA Metiltransferase 3A , DNA Complementar/genética , Éxons , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteína de Leucina Linfoide-Mieloide/genética , Prognóstico , Homologia de Sequência de Aminoácidos
16.
Int J Cancer ; 128(1): 233-8, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20232390

RESUMO

Common genetic variations in genes involved in DNA repair or response to genotoxic stress may influence both cancer susceptibility and treatment response individually or interactively. However, in acute myeloid leukemia (AML), the relevance of these genetic variations remains to be fully established. In this study, we analyzed 42 genetic variations among 15 candidate genes in 307 AML patients and 560 age-sex matched controls. Their associations with chemotherapy response were further evaluated in combination with other well-established prognostic factors. An increased risk of AML was found in individuals heterozygous for XPD 2251A>C (rs13181) with an odds ratio (OR) of 1.637 (95% confidence interval [CI]: 1.118-2.395), and the increased risk could be attributed to C allele (OR = 1.505, 95% CI: 1.061-2.134). Postchemotherapy response analysis revealed that AML patients heterozygous for ATM 4138C>T (rs3092856) or GG homozygous for TP53 215C>G (rs1042522) were independently linked to inferior treatment outcomes. These results uncover novel prognostic factors for AML patients treated with chemotherapy and may also indicate an etiological role of XPD in this disease.


Assuntos
Reparo do DNA/genética , Predisposição Genética para Doença/genética , Leucemia Mieloide/genética , Polimorfismo de Nucleotídeo Único , Doença Aguda , Adolescente , Adulto , Idoso , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Feminino , Variação Genética , Humanos , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/patologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Adulto Jovem
17.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 18(5): 1138-42, 2010 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-21129247

RESUMO

This study was aimed to investigate the clinical feasibility of using multiplex PT-PCR assay for screening rare/cryptic chromosome translocations in patients with de novo acute myeloid leukemia. For 126 patients with de novo AML-M4/M5 without common chromosome translocations including t(15;17), t(8;21) and t(16;16), 3 parallel multiplex RT-PCR assays were set up to detect 6 mll-related gene rearrangements (mll/af10, mll/af17, mll/ell, mll/af9, mll/af6 and mll/enl) with low detection rate and 4 rare fusion genes (dek/can, tls/erg, aml1/mds (evi1) and npm/mlf1). The results showed that 11 patients with positive result from 126 patients were detected which involved in 5 molecular abnormalities. Among them, 10 cases were AML-M5 (16.67%), 1 cases AML-M4 (1.51%). The marker chromosomes were observed in 2 cases out of 11 cases through conventional karyotyping analysis, the karyotyping analysis in 1 case was not performed because this case had 1 mitotic figure only, no any cytogenetic aberrations were found in other 8 cases through R-band karyotyping analysis. It is concluded that multiplex RT-PCR designed in this study can quickly, effectively and accurately identify the rare/cryptic chromosome translocations and can be used in clinical detection.


Assuntos
Rearranjo Gênico , Leucemia Mieloide Aguda/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Translocação Genética , Bandeamento Cromossômico , Testes Genéticos , Humanos
18.
PLoS One ; 5(3): e9821, 2010 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-20352109

RESUMO

To determine whether genetic heterogeneity exists in patients with Graves' disease (GD), the cytotoxic T-lymphocyte associated 4 (CTLA-4) gene, which is implicated a susceptibility gene for GD by considerable genetic and immunological evidence, was used for association analysis in a Chinese Han cohort recruited from various geographic regions. Our association study for the SNPs in the CTLA4 gene in 2640 GD patients and 2204 control subjects confirmed that CTLA4 is the susceptibility gene for GD in the Chinese Han population. Moreover, the logistic regression analysis in the combined Chinese Han cohort revealed that SNP rs231779 (allele frequencies p = 2.81x10(-9), OR = 1.35, and genotype distributions p = 2.75x10(-9), OR = 1.42) is likely the susceptibility variant for GD. Interestingly, the logistic regression analysis revealed that SNP rs35219727 may be the susceptibility variant to GD in the Shandong population; however, SNP, rs231779 in the CTLA4 gene probably independently confers GD susceptibility in the Xuzhou and southern China populations. These data suggest that the susceptibility variants of the CTLA4 gene varied between the different geographic populations with GD.


Assuntos
Antígenos CD/genética , Doença de Graves/etnologia , Doença de Graves/genética , Antígeno CTLA-4 , Estudos de Casos e Controles , China , Estudos de Coortes , Reações Falso-Positivas , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Geografia , Humanos , Modelos Genéticos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Análise de Regressão
19.
Zhonghua Xue Ye Xue Za Zhi ; 30(9): 622-5, 2009 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-19954624

RESUMO

OBJECTIVE: To evaluate the relationship between five single nucleotide polymorphism loci in the MGMT, XPA, XPD and XPG genes and the prevalence of non-Hodgkin's lymphoma. METHODS: A case-control study of 73 lymphoma cases and 500 healthy controls was conducted and the Mass-ARRAY method was applied for detection of MGMT L84F, MGMT K178R, XPA TSS+62, XPD K751Q and XPG TSS+372. RESULTS: MGMT L84F (T allele) was associated with an increased risk of non-Hodgkin lymphoma (OR=2.085, 95%CI=1.069-4.068, P=0.029), mainly in B-cell lymphoma, of which the risk increased by 2.403-fold (OR=2.403, 95%CI=1.103-5.235, P=0.024). No statistically significance was found for MGMT K178R, XPA TSS+62, XPD K751Q and XPG TSS+372. CONCLUSION: Single nucleotide polymorphism in the MGMT gene may closely related to the occurrence of non-Hodgkin lymphoma, especially of B-cell subtype.


Assuntos
Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Linfoma não Hodgkin/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
20.
Leuk Res ; 33(8): 1141-3, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19304323

RESUMO

Chronic myeloid leukemia (CML) progression is characterized by occurrence of new cytogenetic and molecular abnormalities. In the previous study, we have shown the important role of GATA-2 L359 V mutation in CML progression. To further ascertain the truth of transcription factor GATA-2 in hematological malignancies, we expanded our study to GATA-2 full length by directly sequencing and applied MassARRAY assay into GATA-2 L359 V mutation analysis. Finally, no GATA-2 L359 V mutation was found in 270 acute myeloid leukemia, 30 myelodysplastic syndrome, 50 acute lymphoblastic leukemia, 12 chronic lymphocytic leukemia, 40 CML chronic phase and 286 BCR/ABL negative myeloproliferative disorders except CML blast crisis. A new variation of GATA-2 resulted in P250A change was identified, which was not found to have statistical difference between patients with hematological malignancies and healthy control. Hence, we concluded GATA-2 L359 V is exclusively associated with CML progression but not other hematological malignancies and P250A is a new single nucleotide polymorphism.


Assuntos
Substituição de Aminoácidos , Crise Blástica/genética , Fator de Transcrição GATA2/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Crise Blástica/metabolismo , Análise Mutacional de DNA , Progressão da Doença , Feminino , Fator de Transcrição GATA2/metabolismo , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino
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