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1.
Epileptic Disord ; 22(1): 83-89, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32043469

RESUMO

Lacosamide (LCM) is a well-tolerated and increasingly used second-generation AED, and side effects such as atrial fibrillation are rare and poorly characterized. Supported by a literature review, we share our experience of the management of the first reported case of cardioembolic cerebral infarcts in the context of de novo atrial fibrillation, which appeared following a 200-mg intravenous infusion of LCM for the treatment of non-convulsive status epilepticus. Case report and literature review using search items including "atrial fibrillation OR atrial flutter AND LCM" in the thesaurus of Medline. We found three cases of atrial fibrillation/atrial flutter secondary to LCM, one following a 200-mg intravenous infusion. In one patient, previous risk factors for atrial fibrillation were reported and another was started on warfarin; all required suspension of LCM for cessation of atrial fibrillation. Previous risk factors for atrial fibrillation in our patient were older age, male gender, obesity, hypertension, valvular disease, first-degree atrioventricular block and left anterior fascicle block. Atrial fibrillation appeared at the end of the infusion and ceased after a loading dose of amiodarone and suspension of LCM. Apixaban was initiated indefinitely five days later, and MRI showed four acute silent infarctions. The appearance of atrial fibrillation has severe therapeutic and clinical implications and the use of LCM might be reconsidered within a context of increased predisposition to developing atrial fibrillation. If atrial fibrillation appears, the drug should be discontinued and anticoagulation should be considered according to embolic risk. Further investigation is needed in order to better categorize the risk profile of lacosamide regarding atrial fibrillation.

2.
Leukemia ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974435

RESUMO

The deletion of 11q (del(11q)) invariably comprises ATM gene in chronic lymphocytic leukemia (CLL). Concomitant mutations in this gene in the remaining allele have been identified in 1/3 of CLL cases harboring del(11q), being the biallelic loss of ATM associated with adverse prognosis. Although the introduction of targeted BCR inhibition has significantly favored the outcomes of del(11q) patients, responses of patients harboring ATM functional loss through biallelic inactivation are unexplored, and the development of resistances to targeted therapies have been increasingly reported, urging the need to explore novel therapeutic approaches. Here, we generated isogenic CLL cell lines harboring del(11q) and ATM mutations through CRISPR/Cas9-based gene-editing. With these models, we uncovered a novel therapeutic vulnerability of del(11q)/ATM-mutated cells to dual BCR and PARP inhibition. Ex vivo studies in the presence of stromal stimulation on 38 CLL primary samples confirmed a synergistic action of the combination of olaparib and ibrutinib in del(11q)/ATM-mutated CLL patients. In addition, we showed that ibrutinib produced a homologous recombination repair impairment through RAD51 dysregulation, finding a synergistic link of both drugs in the DNA damage repair pathway. Our data provide a preclinical rationale for the use of this combination in CLL patients with this high-risk cytogenetic abnormality.

3.
Cancers (Basel) ; 11(12)2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31795313

RESUMO

Early-onset colorectal cancer (EOCRC) is an increasing and worrisome entity. The aim of this study was to analyze its association with polyps concerning prognosis and surveillance. EOCRC cases were compared regarding the presence or absence of associated polyps (clinical and molecular features), during a minimum of 7 years of follow-up. Of 119 cases, 56 (47%) did not develop polyps (NP group), while 63 (53%) did (P group). The NP group showed a predominant location of the CRC in the rectum (50%), of sporadic cases (54%), and diagnosis at advanced stages: Only P53 and SMARCB1 mutations were statistically linked to this group. The P group, including mainly early-diagnosed tumors, was linked with the most frequent and differential altered chromosomal regions in the array comparative genomic hybridization. The two most frequent groups according to the follow-up were the NP group (40%), and patients developing polyps in the first 5 years of follow-up (P < 5FU) (34%) (these last groups predominantly diagnosed at the earliest stage and with adenomatous polyps (45%)). EOCRC with polyps that developed during the entire follow-up (PDFU group) were mainly located in the right colon (53%), diagnosed in earlier stages, and 75% had a familial history of CRC. Patients developing polyps after the first 5 years (P > 5FU) showed a mucinous component (50%). Our results show that the absence or presence of polyps in EOCRC is an important prognostic factor with differential phenotypes. The development of polyps during surveillance shows that it is necessary to extend the follow-up time, also in those cases with microsatellite-stable EOCRC.

6.
Int J Biol Macromol ; 125: 1275-1288, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30243998

RESUMO

Over a quarter million of protein phosphorylation sites have been identified so far, although the effects of site-specific phosphorylation on protein function and stability, as well as their possible impact in the phenotypic manifestation in genetic diseases are vastly unknown. We investigated here the effects of phosphorylating S82 in human NADP(H):quinone oxidoreductase 1, a representative example of disease-associated flavoprotein in which protein stability is coupled to the intracellular flavin levels. Additionally, the cancer-associated P187S polymorphism causes inactivation and destabilization of the enzyme. By using extensive in vitro and in silico characterization of phosphomimetic S82D mutations, we showed that S82D locally affected the flavin binding site of the wild-type (WT) and P187S proteins thus altering flavin binding affinity, conformational stability and aggregation propensity. Consequently, the phosphomimetic S82D may destabilize the WT protein intracellularly by promoting the formation of the degradation-prone apo-protein. Noteworthy, WT and P187S proteins respond differently to the phosphomimetic mutation in terms of intracellular stability, further supporting differences in molecular recognition of these two variants by the proteasomal degradation pathway. We propose that phosphorylation could have critical consequences on stability and function of human flavoproteins, important for our understanding of genotype-phenotype relationships in their related genetic diseases.


Assuntos
Flavina-Adenina Dinucleotídeo/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Neoplasias/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular , Biologia Computacional/métodos , Flavina-Adenina Dinucleotídeo/química , Humanos , Cinética , Simulação de Dinâmica Molecular , Mutação , NAD(P)H Desidrogenase (Quinona)/química , NAD(P)H Desidrogenase (Quinona)/genética , Fosforilação , Ligação Proteica , Desnaturação Proteica , Estabilidade Proteica , Proteoma , Proteômica/métodos
7.
BMC Med Genomics ; 12(1): 167, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-32293439

RESUMO

BACKGROUND: Since 1969, 49 cases have been presented on ring chromosome 4. All of these cases have been characterized for the loss of genetic material. The genes located in these chromosomal regions are related to the phenotype. CASE PRESENTATION: A 10-year-old Ecuadorian Mestizo girl with ring chromosome 4 was clinically, cytogenetically and molecularly analysed. Clinical examination revealed congenital anomalies, including microcephaly, prominent nose, micrognathia, low set ears, bilateral clinodactyly of the fifth finger, small sacrococcygeal dimple, short stature and mental retardation. Cytogenetic studies showed a mosaic karyotype, mos 46,XX,r(4)(p16.3q35.2)/46,XX, with a ring chromosome 4 from 75 to 79% in three studies conducted over ten years. These results were confirmed by fluorescence in situ hybridization (FISH). Loss of 1.7 Mb and gain of 342 kb in 4p16.3 and loss of 3 Mb in 4q35.2 were identified by high-resolution mapping array. CONCLUSION: Most cases with ring chromosome 4 have deletion of genetic material in terminal regions; however, our case has inv dup del rearrangement in the ring chromosome formation. Heterogeneous clinical features in all cases reviewed are related to the amount of genetic material lost or gained. The application of several techniques can increase our knowledge of ring chromosome 4 and its deviations from typical "ring syndrome."

8.
J Med Case Rep ; 12(1): 340, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30442194

RESUMO

BACKGROUND: Ring chromosome 15 has been associated in previous studies with different clinical characteristic such as cardiac problems, digit and musculoskeletal abnormalities, and mental and motor problems among others. Only 97 clinical cases of ring chromosome 15 syndrome have been reported since 1966 and a common phenotype for these patients has not been established. CASE PRESENTATION: The present case report describes a 15-month-old girl from the Amazon region of Ecuador, of Mestizo ancestry, who after cytogenetic tests showed a 46,XX,r(15) karyotype in more than 70% of metaphases observed. Her parents were healthy and non-related. The pregnancy was complicated and was positive for intrauterine growth retardation. Her birth weight was 1950 g, her length was 43.5 cm, and she had a head circumference of 29.3. In addition to postnatal growth delay, she had scant frontal hair, small eyes, hypertelorism, low-set of ears, flattened nasal bridge, anteverted nostrils, down-turned mouth, three café au lait spots, and delayed dentition. CONCLUSIONS: Despite the frequency of some phenotypes expressed in the different clinical cases reviewed and the present case, a common phenotype for patients with ring 15 could not be determined and it is restricted to the region of the chromosome lost during the ring formation.


Assuntos
Anormalidades Múltiplas/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 15/genética , Citogenética , Transtornos do Crescimento/genética , Anormalidades Múltiplas/diagnóstico , Aberrações Cromossômicas , Feminino , Humanos , Lactente , Cariotipagem , Fenótipo , Cromossomos em Anel , Síndrome
9.
Oncotarget ; 9(20): 15302-15311, 2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29632645

RESUMO

Background: Since there is a predilection of some clinical and molecular features for a given tumor location, we assessed whether this can be confirmed in late-onset colorectal cancer (LOCRC). Results: Right colon cancers showed features associated with sporadic Microsatellite Instability: predominance of female cases and BRAF mutations, and an important mucinous component. Left colon cancers developed a higher number of polyps and multiple primary CRCs, showed the strongest familial component, and had better prognosis. Rectal cancers showed a predominantly sporadic phenotype, with worse prognosis and a CpG Island Methylator Phenotype (CIMP)-High. No copy number alterations (CNAs) greater than or equal to 50% were observed in this LOCRC group, and the most recurrent alterations were losses at 5q13 and 14q11, and gains at 7q11, 7q21-q22, 19p13-p12, 19q13 and 20p11-q11. KRAS and PIK3CA were the only mutated genes showing differences according to the tumor location, mainly for right colon cancers. Materials and Methods: We analyzed clinical and molecular characteristics of LOCRC at different tumor locations in order to determine if there are differential phenotypes related with the location in the colon. Conclusions: Categorizing LOCRC according to tumor location appears to be an adequate first step to resolving the heterogeneity of this subset of CRC.

10.
Oncotarget ; 8(15): 24429-24436, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28416736

RESUMO

To characterize clinical features of a recurrent alteration in 16p13.12-p13.11 in Colorectal Cancer (CRC), mainly in Early-onset subgroup (EOCRC), and to assess the status of NOMO1, a gene located in that region, we analyzed differential clinicopathological, familial and molecular features of CRC subsets with and without alterations in the 16p13.12-p13.11, in global and EOCRC groups. We confirmed the region by fluorescence in-situ hybridization, and Quantitative Real-Time PCR analyzed the status of NOMO1 in different age-of-onset and Microsatellite Instability (MSI)-status CRC subsets. Both age-of-onset subsets were subsequently extended to further confirm NOMO1 gene changes. 16p13.12-p13.11 alterations were observed in 23.3% of CRCs, and was detected more frequently in EOCRC (33.3%) than in late-onset CRC (16.3%). The group with deletion in 16p showed a higher frequency of females and left-colon locations; a better prognosis; and higher Chromosomal Instability. Within the primary EOCRC population, 34 out of 34 of tumours showed a homozygous deletion in NOMO1, while in the late-onset population only 2 of the 17 tumours (11.7%) showed it. In the extended group, we found 61 out of 75 EOCRC patients (81.3%) with homozygous deletion and 7 patients (9.3%) with heterozygous deletion of NOMO1; moreover, in the new 50 late-onset patients, the proportions of deletions decreased. Microsatellite-Stable (MSS) EOCRC showed a very high proportion of homozygous loss of NOMO1 (54 of 59 cases, 91.5%), while the deletion was observed in only 7 out of 16 MSI cases. Deletion of NOMO1 is a molecular marker predominantly associated with EOCRC, particularly MSS subtypes.


Assuntos
Neoplasias Colorretais/genética , Proteína Nodal/genética , Adulto , Neoplasias Colorretais/patologia , Feminino , Deleção de Genes , Humanos , Masculino , Prognóstico
13.
PLoS One ; 11(2): e0148972, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26872047

RESUMO

UNLABELLED: Identifying additional genetic alterations associated with poor prognosis in acute lymphoblastic leukemia (ALL) is still a challenge. AIMS: To characterize the presence of additional DNA copy number alterations (CNAs) in children and adults with ALL by whole-genome oligonucleotide array (aCGH) analysis, and to identify their associations with clinical features and outcome. Array-CGH was carried out in 265 newly diagnosed ALLs (142 children and 123 adults). The NimbleGen CGH 12x135K array (Roche) was used to analyze genetic gains and losses. CNAs were analyzed with GISTIC and aCGHweb software. Clinical and biological variables were analyzed. Three of the patients showed chromothripsis (cth6, cth14q and cth15q). CNAs were associated with age, phenotype, genetic subtype and overall survival (OS). In the whole cohort of children, the losses on 14q32.33 (p = 0.019) and 15q13.2 (p = 0.04) were related to shorter OS. In the group of children without good- or poor-risk cytogenetics, the gain on 1p36.11 was a prognostic marker independently associated with shorter OS. In adults, the gains on 19q13.2 (p = 0.001) and Xp21.1 (p = 0.029), and the loss of 17p (p = 0.014) were independent markers of poor prognosis with respect to OS. In summary, CNAs are frequent in ALL and are associated with clinical parameters and survival. Genome-wide DNA copy number analysis allows the identification of genetic markers that predict clinical outcome, suggesting that detection of these genetic lesions will be useful in the management of patients newly diagnosed with ALL.


Assuntos
Biomarcadores Tumorais/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Dosagem de Genes , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto Jovem
14.
Clin Cancer Res ; 22(1): 207-17, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26341922

RESUMO

PURPOSE: Dysregulation of one of the three D-cyclin genes has been observed in virtually all multiple myeloma tumors. The mechanisms by which CCND2 is upregulated in a set of multiple myeloma are not completely deciphered. We investigated the role of post-transcriptional regulation through the interaction between miRNAs and their binding sites at 3'UTR in CCND2 overexpression in multiple myeloma. EXPERIMENTAL DESIGN: Eleven myeloma cell lines and 45 primary myeloma samples were included in the study. Interactions between miRNAs deregulated in multiple myeloma and mRNA targets were analyzed by 3'UTR-luciferase plasmid assay. The presence of CCND2 mRNA isoforms different in length was explored using qRT-PCR, Northern blot, mRNA FISH, and 3' rapid amplification of cDNA ends (RACE)-PCR. RESULTS: We detected the presence of short CCND2 mRNA, both in the multiple myeloma cell lines and primary cells. The results obtained by 3'RACE experiments revealed that changes in CCND2 3'UTR length are explained by alternative polyadenylation. The luciferase assays using plasmids harboring the truncated CCND2 mRNA strongly confirmed the loss of miRNA sites in the shorter CCND2 mRNA isoform. Those multiple myelomas with greater abundance of the shorter 3'UTR isoform were associated with significant higher level of total CCND2 mRNA expression. Furthermore, functional analysis showed significant CCND2 mRNA shortening after CCND1 silencing and an increased relative expression of longer isoform after CCND1 and CCND3 overexpression, suggesting that cyclin D1 and D3 could regulate CCND2 levels through modifications in polyadenylation-cleavage reaction. CONCLUSIONS: Overall, these results highlight the impact of CCND2 3'UTR shortening on miRNA-dependent regulation of CCND2 in multiple myeloma.


Assuntos
Ciclina D2/genética , Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/genética , Processamento Pós-Transcricional do RNA , Regiões 3' não Traduzidas , Processamento Alternativo , Linhagem Celular Tumoral , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina D2/metabolismo , Ciclina D3/genética , Ciclina D3/metabolismo , Metilação de DNA , Humanos , MicroRNAs/genética , Mieloma Múltiplo/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Translocação Genética , Regulação para Cima
15.
BMC Cancer ; 15: 238, 2015 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-25880332

RESUMO

BACKGROUND: MicroRNAs are known to inhibit gene expression by binding to the 3'UTR of the target transcript. Downregulation of miR-223 has been recently reported to have prognostic significance in CLL. However, there is no evidence of the pathogenetic mechanism of this miRNA in CLL patients. METHODS: By applying next-generation sequencing techniques we have detected a common polymorphism (rs2307842), in 24% of CLL patients, which disrupts the binding site for miR-223 in HSP90B1 3'UTR. We investigated whether miR-223 directly targets HSP90B1 through luciferase assays and ectopic expression of miR-223. Quantitative real-time polymerase chain reaction and western blot were used to determine HSP90B1 expression in CLL patients. The relationship between rs2307842 status, HSP90B1 expression and clinico-biological data were assessed. RESULTS: HSP90B1 is a direct target for miR-223 by interaction with the putative miR-223 binding site. The analysis in paired samples (CD19+ fraction cell and non-CD19+ fraction cell) showed that the presence of rs2307842 and IGHV unmutated genes determined HSP90B1 overexpression in B lymphocytes from CLL patients. These results were confirmed at the protein level by western blot. Of note, HSP90B1 overexpression was independently predictive of shorter time to the first therapy in CLL patients. By contrast, the presence of rs2307842 was not related to the outcome. CONCLUSIONS: HSP90B1 is a direct target gene of miR-223. Our results provide a plausible explanation of why CLL patients harboring miR-223 downregulation are associated with a poor outcome, pointing out HSP90B1 as a new pathogenic mechanism in CLL and a promising therapeutic target.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Glicoproteínas de Membrana/genética , MicroRNAs/genética , Análise de Sequência de DNA/métodos , Regiões 3' não Traduzidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Sítios de Ligação , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , MicroRNAs/química , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico
16.
World J Gastroenterol ; 20(46): 17288-96, 2014 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-25516639

RESUMO

Colorectal cancer (CRC) has a great impact on the world population. With increasing frequency, CRC is described according to the presenting phenotype, based on its molecular characteristics. Classification of CRC tumors according to their genetic and/or epigenetic alterations is not only important for establishing the molecular bases of the disease, but also for predicting patient outcomes and developing more individualized treatments. Early-onset CRC is a heterogeneous disease, with a strong familial component, although the disease is sporadic in an important proportion of cases. Different molecular alterations appear to contribute to the apparent heterogeneity of the early-onset population and subgroups can be distinguished with distinct histopathologic and familial characteristics. Moreover, compared with late-onset CRC, there are characteristics that suggest that early-onset CRC may have a different molecular basis. The purpose of this review was to analyze the current state of knowledge about early-onset CRC with respect to clinicopathologic, familial and molecular features. Together, these features make it increasingly clear that this subset of CRC may be a separate disease, although it has much in common with late-onset CRC.


Assuntos
Neoplasias Colorretais/diagnóstico , Biomarcadores Tumorais/genética , Neoplasias Colorretais/classificação , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Predisposição Genética para Doença , Humanos , Técnicas de Diagnóstico Molecular , Estadiamento de Neoplasias , Linhagem , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco
18.
Eur J Haematol ; 93(5): 422-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24813417

RESUMO

To assess the presence of genetic imbalances in patients with myeloproliferative neoplasms (MPNs), 38 patients with chronic eosinophilia were studied by array comparative genomic hybridization (aCGH): seven had chronic myelogenous leukaemia (CML), BCR-ABL1 positive, nine patients had myeloproliferative neoplasia Ph- (MPN-Ph-), three had a myeloid neoplasm associated with a PDGFRA rearrangement, and the remaining two cases were Lymphoproliferative T neoplasms associated with eosinophilia. In addition, 17 patients had a secondary eosinophilia and were used as controls. Eosinophilic enrichment was carried out in all cases. Genomic imbalances were found in 76% of all MPN patients. Losses on 20q were the most frequent genetic abnormality in MPNs (32%), affected the three types of MPN studied. This study also found losses at 11q13.3 in 26% of patients with MPN-Ph- and in 19p13.11 in two of the three patients with an MPN associated with a PDGFRA rearrangement. In addition, 29% of patients with CML had losses on 8q24. In summary, aCGH revealed clonality in eosinophils in most MPNs, suggesting that it could be a useful technique for defining clonality in these diseases. The presence of genetic losses in new regions could provide new insights into the knowledge of these MPN associated with eosinophilia.


Assuntos
Aberrações Cromossômicas , Eosinofilia/genética , Eosinófilos/metabolismo , Genoma , Neoplasias Hematológicas/genética , Transtornos Mieloproliferativos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cromossomos Humanos Par 11/química , Cromossomos Humanos Par 19/química , Cromossomos Humanos Par 20/química , Cromossomos Humanos Par 8/química , Doença Crônica , Células Clonais , Hibridização Genômica Comparativa , Eosinofilia/diagnóstico , Eosinofilia/patologia , Eosinófilos/patologia , Feminino , Proteínas de Fusão bcr-abl/genética , Instabilidade Genômica , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética
19.
Biomed Res Int ; 2014: 814294, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24693539

RESUMO

TET2 is involved in a variety of hematopoietic malignancies, mainly in myeloid malignancies. Most mutations of TET2 have been identified in myeloid disorders, but some have also recently been described in mature lymphoid neoplasms. In contrast to the large amount of data about mutations of TET2, some data are available for gene expression. Moreover, the role of TET2 in chronic lymphocytic leukemia (CLL) is unknown. This study analyzes both TET2 expression and mutations in 48 CLL patients. TET2 expression was analyzed by exon arrays and quantitative real-time polymerase chain reaction (qRT-PCR). Next-generation sequencing (NGS) technology was applied to investigate the presence of TET2 variations. Overexpression of TET2 was observed in B-cell lymphocytes from CLL patients compared with healthy donors (P = 0.004). In addition, in CLL patients, an overexpression of TET2 was also observed in the clonal B cells compared with the nontumoral cells (P = 0.002). However, no novel mutations were observed. Therefore, overexpression of TET2 in CLL seems to be unrelated to the presence of genomic TET2 variations.


Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/metabolismo , Estudos de Casos e Controles , Células Clonais , Feminino , Regulação Leucêmica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade
20.
Gene ; 536(1): 79-83, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24325908

RESUMO

BACKGROUND: Glioblastoma is the most common and aggressive primary brain tumor in adults. Despite several factors such as ionizing radiation exposure or rare genetic syndromes have been associated with the development of glioblastoma, no underlying cause has been identified for the majority of cases. We thus aimed to investigate the role of DNA repair polymorphisms in modulating glioblastoma risk. METHODS: Genotypic and allelic frequencies of seven common polymorphisms in DNA repair genes involved in nucleotide excision repair (ERCC1 rs11615, ERCC2 rs13181, ERCC6 rs4253079), base excision repair (APEX1 rs1130409, XRCC1 rs25487), double-strand break repair (XRCC3 rs861539) and mismatch repair (MLH1 rs1800734) pathways were analyzed in 115 glioblastoma patients and 200 healthy controls. Haplotype analysis was also performed for ERCC1 rs11615 and ERCC2 rs13181 polymorphisms, located on the same chromosomal region (19q13.32). RESULTS: Our results indicated that carriers of the ERCC2 Gln/Gln genotype were associated with a lower glioblastoma risk (OR=0.32, 95% CI 0.12-0.89; P=0.028), whereas carriers of the MLH1 AA genotype were associated with an increased risk of glioblastoma (OR=3.14, 95% CI 1.09-9.06; P=0.034). Furthermore, the haplotype containing the C allele of ERCC2 rs13181 polymorphism and the T allele of ERCC1 rs11615 polymorphism was significantly associated with a protective effect of developing glioblastoma (OR=0.34, 95% CI 0.16-0.71; P=0.004). CONCLUSIONS: These results pointed out that MLH1 rs1800734 and ERCC2 rs13181 polymorphisms might constitute glioblastoma susceptibility factors, and also suggested that the chromosomal region 19q could be important in glioblastoma pathogenesis.


Assuntos
Neoplasias Encefálicas/genética , Reparo do DNA/genética , Glioblastoma/genética , Polimorfismo Genético , Idoso , Neoplasias Encefálicas/epidemiologia , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Glioblastoma/epidemiologia , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade
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