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1.
JCI Insight ; 5(1)2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31941838

RESUMO

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by cytopenia and extramedullary hematopoiesis, resulting in splenomegaly. Multiple pathological mechanisms (e.g., circulating cytokines and genetic alterations, such as JAKV617F mutation) have been implicated in the etiology of MF, but the molecular mechanism causing resistance to JAK2V617F inhibitor therapy remains unknown. Among MF patients who were treated with the JAK inhibitor ruxolitinib, we compared noncoding RNA profiles of ruxolitinib therapy responders versus nonresponders and found miR-543 was significantly upregulated in nonresponders. We validated these findings by reverse transcription-quantitative PCR. in this same cohort, in 2 additional independent MF patient cohorts from the United States and Romania, and in a JAK2V617F mouse model of MF. Both in vitro and in vivo models were used to determine the underlying molecular mechanism of miR-543 in MF. Here, we demonstrate that miR-543 targets the dioxygenases ten-eleven translocation 1 (TET1) and 2 (TET2) in patients and in vitro, causing increased levels of global 5-methylcytosine, while decreasing the acetylation of histone 3, STAT3, and tumor protein p53. Mechanistically, we found that activation of STAT3 by JAKs epigenetically controls miR-543 expression via binding the promoter region of miR-543. Furthermore, miR-543 upregulation promotes the expression of genes related to drug metabolism, including CYP3A4, which is involved in ruxolitinib metabolism. Our findings suggest miR-543 as a potentially novel biomarker for the prognosis of MF patients with a high risk of treatment resistance and as a potentially new target for the development of new treatment options.

3.
Sci Rep ; 9(1): 9020, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227763

RESUMO

The cancer-predisposing syndrome caused by biallelic mutations in NTHL1 may not be a solely colorectal cancer (CRC) and polyposis syndrome but rather a multi-tumor recessive disease. The presence of ≤10 adenomas in several mutation carriers suggests a possible causal role of NTHL1 in hereditary or early-onset nonpolyposis CRC. The involvement of NTHL1 in serrated/hyperplastic polyposis remains unexplored. The aim of our study is to elucidate the role of NTHL1 in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated polyposis. NTHL1 mutational screening was performed in 312 cancer patients with personal or family history of multiple tumor types, 488 with hereditary nonpolyposis CRC, and 96 with serrated/hyperplastic polyposis. While no biallelic mutation carriers were identified in patients with personal and/or family history of multiple tumor types or with serrated polyposis, one was identified among the 488 nonpolyposis CRC patients. The carrier of c.268C>T (p.Q90*) and 550-1G>A was diagnosed with CRC and meningioma at ages 37 and 45 respectively, being reclassified as attenuated adenomatous polyposis after the cumulative detection of 26 adenomas. Our findings suggest that biallelic mutations in NTHL1 rarely cause CRC, a personal/familial multi-tumor history, or serrated polyposis, in absence of adenomas.

4.
Mol Aspects Med ; 69: 27-40, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30935834

RESUMO

Most next generation sequencing (NGS) studies identified candidate genetic variants predisposing to colorectal cancer (CRC) but do not tackle its functional interpretation to unequivocally recognize a new hereditary CRC gene. Besides, germline variants in already established hereditary CRC-predisposing genes or somatic variants share the same need when trying to categorize those with relevant significance. Functional genomics approaches have an important role in identifying the causal links between genetic architecture and phenotypes, in order to decipher cellular function in health and disease. Therefore, functional interpretation of identified genetic variants by NGS platforms is now essential. Available approaches nowadays include bioinformatics, cell and molecular biology and animal models. Recent advances, such as the CRISPR-Cas9, ZFN and TALEN systems, have been already used as a powerful tool with this objective. However, the use of cell lines is of limited value due to the CRC heterogeneity and its close interaction with microenvironment. Access to tridimensional cultures or organoids and xenograft models that mimic the in vivo tissue architecture could revolutionize functional analysis. This review will focus on the application of state-of-the-art functional studies to better tackle new genes involved in germline predisposition to this neoplasm.

5.
Cancer Lett ; 447: 86-92, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30677446

RESUMO

Somatic epigenetic inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) is frequent in colorectal cancer (CRC); however, its involvement in CRC predisposition remains unexplored. We assessed the role and relevance of MGMT germline mutations and epimutations in familial and early-onset CRC. Mutation and promoter methylation screenings were performed in 473 familial and/or early-onset mismatch repair-proficient nonpolyposis CRC cases. No constitutional MGMT inactivation by promoter methylation was observed. Of six rare heterozygous germline variants identified, c.346C > T (p.H116Y) and c.476G > A (p.R159Q), detected in three and one families respectively, affected highly conserved residues and showed segregation with cancer in available family members. In vitro, neither p.H116Y nor p.R159Q caused statistically significant reduction of MGMT repair activity. No evidence of somatic second hits was found in the studied tumors. Case-control data showed over-representation of c.346C > T (p.H116Y) in familial CRC compared to controls, but no overall association of MGMT mutations with CRC predisposition. In conclusion, germline mutations and constitutional epimutations in MGMT are not major players in hereditary CRC. Nevertheless, the over-representation of c.346C > T (p.H116Y) in our familial CRC cohort warrants further research.


Assuntos
Neoplasias Colorretais/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Células Germinativas/fisiologia , Mutação em Linhagem Germinativa/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Adulto Jovem
6.
Front Med (Lausanne) ; 5: 247, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364207

RESUMO

Background: Eosinophilic esophagitis (EoE) was first described in the 1990s, showing an increasing incidence and prevalence since then, being the leading cause of food impaction and the major cause of dysphagia. Probably, in a few years, EoE may no longer be considered a rare disease. Methods: This article discusses new aspects of the pathogenesis, symptoms, diagnosis, and treatment of EoE according to the last published guidelines. Results: The epidemiological studies indicate a multifactorial origin for EoE, where environmental and genetic factors take part. EoE affects both children and adults and it is frequently associated with atopic disease and IgE-mediated food allergies. In patients undergoing oral immunotherapy for desensitization from IgE-mediated food allergy the risk of developing EoE is 2.72%. Barrier dysfunction and T-helper 2 inflammation is considered to be pathogenetically important factors. There are different patterns of clinical presentation varying with age and can be masked by adaptation habits. Besides, symptoms do not usually correlate with histologic disease activity. The diagnostic criteria for EoE has evolved but mainly requires symptoms of esophageal dysfunction with histologic evidence of a peak value of at least 15 eosinophils per high-power field. Endoscopies have to be repeated in order to diagnose, monitor, and treat EoE. Treatment of EoE can be started either by drugs (PPIs and topical corticosteroids) or elimination diets. The multistage step-up elimination diet management approach of EoE is promising. Endoscopic dilation is used for patients with severe dysphagia/food impaction with inadequate response to anti-inflammatory treatment. Conclusions: Research in recent years has contributed to a better understanding of EoE's pathogenesis, genetic background, natural history, allergy workup, standardization in assessment of disease activity, evaluation of minimally invasive diagnostic tools, and new therapeutic approaches. However, several unmet needs are to be solved urgently, as finding a non-invasive disease-monitoring methods and biomarkers for routine practice, the development or new therapies, novel food allergy testing to detect triggering foods, drug, and doses required for initial therapy and safety issues with long-term maintenance therapy, amongst others. Besides, multidisciplinary management units of EoE, involving gastroenterologists, pediatricians, allergists, pathologists, dietitians, and ENT specialists are needed.

7.
Hum Mutat ; 39(9): 1214-1225, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29900613

RESUMO

The causal association of NUDT1 (=MTH1) and OGG1 with hereditary colorectal cancer (CRC) remains unclear. Here, we sought to provide additional evidence for or against the causal contribution of NUDT1 and OGG1 mutations to hereditary CRC and/or polyposis. Mutational screening was performed using pooled DNA amplification and targeted next-generation sequencing in 529 families (441 uncharacterized MMR-proficient familial nonpolyposis CRC and 88 polyposis cases). Cosegregation, in silico analyses, in vitro functional assays, and case-control associations were carried out to characterize the identified variants. Five heterozygous carriers of novel (n = 1) or rare (n = 4) NUDT1 variants were identified. In vitro deleterious effects were demonstrated for c.143G>A p.G48E (catalytic activity and protein stability) and c.403G>T p.G135W (protein stability), although cosegregation data in the carrier families were inconclusive or nonsupportive. The frequency of missense, loss-of-function, and splice-site NUDT1 variants in our familial CRC cohort was similar to the one observed in cancer-free individuals, suggesting lack of association with CRC predisposition. No OGG1 pathogenic mutations were identified. Our results suggest that the contribution of NUDT1 and OGG1 germline mutations to hereditary CRC and to polyposis is inexistent or, at most, negligible. The inclusion of these genes in routine genetic testing is not recommended.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Glicosilases/genética , Enzimas Reparadoras do DNA/genética , Monoéster Fosfórico Hidrolases/genética , Polipose Adenomatosa do Colo/patologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo do DNA/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética/genética , Genótipo , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação com Perda de Função/genética , Masculino , Mutação de Sentido Incorreto/genética , Estresse Oxidativo , Isoformas de Proteínas/genética
8.
Mol Cancer ; 17(1): 23, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29448935

RESUMO

Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC.


Assuntos
Polipose Adenomatosa do Colo/genética , Proteínas de Ciclo Celular/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação em Linhagem Germinativa , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas Serina-Treonina Quinases/genética , Fuso Acromático/genética , Proteínas de Ciclo Celular/química , Humanos , Modelos Moleculares , Linhagem , Proteínas de Ligação a Poli-ADP-Ribose/química , Conformação Proteica , Proteínas Serina-Treonina Quinases/química
10.
Gastroenterology ; 154(1): 181-194.e20, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28912018

RESUMO

BACKGROUND & AIMS: Although there is a genetic predisposition to colorectal cancer (CRC), few of the genes that affect risk have been identified. We performed whole-exome sequence analysis of individuals in a high-risk family without mutations in genes previously associated with CRC risk to identify variants associated with inherited CRC. METHODS: We collected blood samples from 3 relatives with CRC in Spain (65, 62, and 40 years old at diagnosis) and performed whole-exome sequence analyses. Rare missense, truncating or splice-site variants shared by the 3 relatives were selected. We used targeted pooled DNA amplification followed by next generation sequencing to screen for mutations in candidate genes in 547 additional hereditary and/or early-onset CRC cases (502 additional families). We carried out protein-dependent yeast growth assays and transfection studies in the HT29 human CRC cell line to test the effects of the identified variants. RESULTS: A total of 42 unique or rare (population minor allele frequency below 1%) nonsynonymous genetic variants in 38 genes were shared by all 3 relatives. We selected the BRF1 gene, which encodes an RNA polymerase III transcription initiation factor subunit for further analysis, based on the predicted effect of the identified variant and previous association of BRF1 with cancer. Previously unreported or rare germline variants in BRF1 were identified in 11 of 503 CRC families, a significantly greater proportion than in the control population (34 of 4300). Seven of the identified variants (1 detected in 2 families) affected BRF1 mRNA splicing, protein stability, or expression and/or function. CONCLUSIONS: In an analysis of families with a history of CRC, we associated germline mutations in BRF1 with predisposition to CRC. We associated deleterious BRF1 variants with 1.4% of familial CRC cases, in individuals without mutations in high-penetrance genes previously associated with CRC. Our findings add additional evidence to the link between defects in genes that regulate ribosome synthesis and risk of CRC.


Assuntos
Neoplasias Colorretais/genética , Mutação em Linhagem Germinativa/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Adulto , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Espanha
11.
EBioMedicine ; 20: 182-192, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28465156

RESUMO

Prevalence of Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) varies greatly in different populations. We hypothesized that the actual prevalence of KSHV/HHV8 infection in humans is underestimated by the currently available serological tests. We analyzed four independent patient cohorts with post-surgical or post-chemotherapy sepsis, chronic lymphocytic leukemia and post-surgical patients with abdominal surgical interventions. Levels of specific KSHV-encoded miRNAs were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and KSHV/HHV-8 IgG were measured by immunoassay. We also measured specific miRNAs from Epstein Barr Virus (EBV), a virus closely related to KSHV/HHV-8, and determined the EBV serological status by ELISA for Epstein-Barr nuclear antigen 1 (EBNA-1) IgG. Finally, we identified the viral miRNAs by in situ hybridization (ISH) in bone marrow cells. In training/validation settings using independent multi-institutional cohorts of 300 plasma samples, we identified in 78.50% of the samples detectable expression of at least one of the three tested KSHV-miRNAs by RT-qPCR, while only 27.57% of samples were found to be seropositive for KSHV/HHV-8 IgG (P<0.001). The prevalence of KSHV infection based on miRNAs qPCR is significantly higher than the prevalence determined by seropositivity, and this is more obvious for immuno-depressed patients. Plasma viral miRNAs quantification proved that EBV infection is ubiquitous. Measurement of viral miRNAs by qPCR has the potential to become the "gold" standard method to detect certain viral infections in clinical practice.


Assuntos
MicroRNAs , RNA Viral , Carga Viral , Viroses/sangue , Viroses/virologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Hibridização In Situ , Contagem de Leucócitos , Contagem de Linfócitos , Prevalência , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Viroses/diagnóstico , Viroses/epidemiologia
13.
Expert Rev Clin Immunol ; 13(3): 271-281, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27653257

RESUMO

INTRODUCTION: Work-related asthma includes two subtypes: occupational asthma or asthma caused by specific agents (sensitizers or irritants) in the workplace, and work-exacerbated asthma or pre-existing asthma worsened by workplace exposures. Areas covered: This review provides an update on the definitions and the clinical features of the different work-related asthma subtypes as well as new insights into their etiology and the pathophysiological mechanisms involved. The diagnosis of work-related asthma should be made on objective basis using a constellation of clinical, physiologic and allergologic tests. Specific inhalation challenge with the suspected occupational agent(s) remains as the reference standard for diagnosis. A literature search was performed using the following terms: work-related asthma, occupational asthma, work-exacerbated asthma, irritant-induced asthma and etiological agents. Expert commentary: Studies focusing on the biological effects and mechanisms of environmental exposures in the development of sensitizer-induced or irritant-induced asthma in various workplace settings are of greatest interest. An integrative approach that combines clinical parameters with component-resolved diagnosis as well as inflammatory biomarkers appears to be very promising. Occupational allergy provides a good opportunity to understand the complex relationships between exposure to allergens in the workplace, interaction with genes and the co-exposures to other factors in the working environment.


Assuntos
Asma Ocupacional/diagnóstico , Dermatite Alérgica de Contato/diagnóstico , Alérgenos/imunologia , Animais , Biomarcadores/metabolismo , Testes de Provocação Brônquica , Humanos , Mediadores da Inflamação/metabolismo , Irritantes/imunologia , Exposição Ocupacional/efeitos adversos
15.
Sci Rep ; 6: 20697, 2016 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-26852919

RESUMO

Germline mutations in UNC5C have been suggested to increase colorectal cancer (CRC) risk, thus causing hereditary CRC. However, the evidence gathered thus far is insufficient to include the study of the UNC5C gene in the routine genetic testing of familial CRC. Here we aim at providing a more conclusive answer about the contribution of germline UNC5C mutations to genetically unexplained hereditary CRC and/or polyposis cases. To achieve this goal we sequenced the coding region and exon-intron boundaries of UNC5C in 544 familial CRC or polyposis patients (529 families), using a technique that combines pooled DNA amplification and massively parallel sequencing. A total of eight novel or rare variants, all missense, were identified in eight families. Co-segregation data in the families and association results in case-control series are not consistent with a causal effect for 7 of the 8 identified variants, including c.1882_1883delinsAA (p.A628K), previously described as a disease-causing mutation. One variant, c.2210G > A (p.S737N), remained unclassified. In conclusion, our results suggest that the contribution of germline mutations in UNC5C to hereditary colorectal cancer and to polyposis cases is negligible.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Receptores de Superfície Celular/genética , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Estudos de Casos e Controles , Células Cultivadas , Neoplasias Colorretais/patologia , DNA/química , DNA/genética , DNA/metabolismo , Metilação de DNA , Éxons , Feminino , Mutação em Linhagem Germinativa , Humanos , Perda de Heterozigosidade/genética , Linfócitos/citologia , Linfócitos/metabolismo , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Receptores de Netrina , Linhagem , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Processamento de RNA , Análise de Sequência de DNA
17.
J Neurooncol ; 122(3): 441-50, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25682093

RESUMO

Clinical and molecular prognostic factors in gliomas include age, IDH mutation, the glioma CpG island methylator phenotype (G-CIMP+) and promoter methylation of the O(6)-methylguanine DNA-methyltransferase (MGMT) gene. Among these markers, a predictive value was reported in glioblastomas (GBM) for MGMT promoter methylation, in particular in elderly GBM patients. In this study, methylation data from 46 glioma samples with the Illumina 450K platform were obtained and extended using external data to include a total of 247 glioma samples. Methylation analysis of the whole MGMT gene with this platform revealed two strongly survival-associated CpG regions within the promoter and the gene body, which were confirmed in a reported dataset of high grade-gliomas. Methylation at the promoter (CpG 25, cg12981137 and the prognostic model MGMT-STP27) and at the gene body CpG 165 (cg07933035), were significantly associated with better overall survival, and strongly correlated with G-CIMP+ status. In this series, the prognostic value of MGMT methylation at the promoter was not observed in G-CIMP- cases, although around 50 % of them were MGMT-methylated. These results were also obtained in an homogeneously-treated series of chemoradiated G-CIMP- GBMs analyzed by MSP and qMSP, and confirmed in a reported pyrosequencing-analyzed series of gliomas. Interestingly, in contrast to the MGMT promoter, gene body methylation was of prognostic value in G-CIMP-patients older than 65 years. Our study highlights the relevance of the prognostic value of the different regions of methylation throughout the MGMT gene that could be affected by specific G-CIMP profiles and age groups.


Assuntos
Neoplasias Encefálicas/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/genética , Proteínas Supressoras de Tumor/genética , Adulto , Fatores Etários , Idoso , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Feminino , Perfilação da Expressão Gênica , Glioma/diagnóstico , Glioma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Análise de Componente Principal , Prognóstico , Regiões Promotoras Genéticas/genética , Análise de Sobrevida , Adulto Jovem
18.
J Neuropathol Exp Neurol ; 74(3): 241-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25668564

RESUMO

According to World Health Organization criteria, diffuse gliomas are divided into several histological subtypes, including astrocytomas, oligodendrogliomas, and oligoastrocytomas, and 4 malignancy grades (I-IV). Molecular alterations, such as the isocitrate dehydrogenase gene (IDH) mutation or 1p/19q loss, are found in these tumors but are not included in the current classification system. Recently, mutation of α thalassemia/mental retardation syndrome X-linked (ATRX) gene and its loss of expression have been reported in infiltrating gliomas. We evaluated ATRX protein expression in 272 gliomas and its association with molecular and clinical features. Loss of ATRX expression was more common in tumors with an astrocytic component (astrocytomas II/III, 46.4%; oligoastrocytomas, 47.5%) but was uncommon in oligodendrogliomas (7.3%) and glioblastomas (0.9%). In astrocytic tumors, loss of ATRX expression was significantly associated with longer overall survival. Remarkably, on the basis of IDH mutation, 1p/19q codeletion, and ATRX expression, our study defined 4 molecularly and prognostically different groups of gliomas, showing the relevance of ATRX expression as a new marker for refining the molecular classification of gliomas and for distinguishing clinically distinct prognostic subgroups of patients.


Assuntos
Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/diagnóstico , Glioma/classificação , Glioma/diagnóstico , Bancos de Tecidos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Feminino , Glioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores/classificação , Gradação de Tumores/métodos , Adulto Jovem
19.
Acta Neuropathol ; 126(2): 277-89, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23689617

RESUMO

Oligodendroglial tumors (OTs) are primary brain tumors that show variable clinical and biological behavior. The 1p/19q codeletion is frequent in these tumors, indicating a better prognosis and/or treatment response. Recently, the prognostically favorable CpG island methylator phenotype (CIMP) in gliomas (G-CIMP+) was associated with mutations in the isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH) genes, as opposed to G-CIMP- tumors, highlighting the relevance of epigenetic mechanisms. We performed a whole-genome methylation study in 46 OTs, and a gene expression study of 25 tumors, correlating the methylation and transcriptomic profiles with molecular and clinical variables. Here, we identified two different epigenetic patterns within the previously described main G-CIMP+ profile. Both IDH mutation-associated methylation profiles featured one group of OTs with 1p/19q loss (CD-CIMP+), most of which were pure oligodendrogliomas, and a second group with intact 1p/19q and frequent TP53 mutation (CIMP+), most of which exhibited a mixed histopathology. A third group of OTs lacking the CIMP profile (CIMP-), and with a wild-type IDH and an intact 1p/19q, similar to the G-CIMP- subgroup, was also observed. The three CIMP groups presented a significantly better (CD-CIMP+), intermediate (CIMP+) or worse (CIMP-) prognosis. Furthermore, transcriptomic analyses revealed CIMP-specific gene expression signatures, indicating the impact of genetic status (IDH mutation, 1p/19q codeletion, TP53 mutation) on gene expression, and pointing to candidate biomarkers. Therefore, the CIMP profiles contributed to the identification of subgroups of OTs characterized by different prognoses, histopathologies, molecular features and gene expression signatures, which may help in the classification of OTs.


Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA/genética , Isocitrato Desidrogenase/genética , Oligodendroglioma/genética , Neoplasias Encefálicas/mortalidade , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Estimativa de Kaplan-Meier , Oligodendroglioma/mortalidade , Prognóstico , Transcriptoma , Proteína Supressora de Tumor p53/genética
20.
Eur J Cancer ; 49(7): 1641-53, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23374632

RESUMO

Erlotinib (ERL), a tyrosine kinase inhibitor that acts on the epidermal growth factor receptor (EGFR), is used as a second line treatment for glioma therapy, with controversial findings regarding its response. Here, we analysed the gene expression profiles of a series of human glioma cell lines with differing sensitivities to ERL to identify the gene expression changes associated with ERL response. The varying responses to ERL were associated with different expression levels of specific genes (HRAS, CTFG, ERCC5 and HDAC3) and genes associated with specific pathways (apoptosis and cell death). PI3K pathway genes were primarily affected by ERL, as we found that PIK3R3 was repressed by ERL treatment in sensitive glioma cell lines. The cell cycle and ubiquitin pathways were also affected by EGFR inhibition, as GAS5, PLK1 and BIRC5 were the most significantly affected genes. In this study we have identified several genes such as PIK3R3 and GAS5, that can be targeted in order to enhance the response to ERL therapy.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Quinazolinas/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Análise por Conglomerados , Inibidor p16 de Quinase Dependente de Ciclina/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Receptores ErbB/genética , Cloridrato de Erlotinib , Glioma/genética , Glioma/patologia , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Nucleares/genética , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Survivina , Fatores de Transcrição/genética
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