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1.
Gene ; 710: 333-340, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31202904

RESUMO

Gene promoter methylation is a common epigenetic event, taking place in the early phase of tumorigenesis, which has a great potential as a diagnostic and prognostic cancer biomarker. In this umbrella review, we provide an overview on the association between gene-promoter methylation of protein-coding genes and cancer risk based on currently available meta-analyses data on gene promoter methylation. We searched MEDLINE via PubMed and the Cochrane Database of Systematic Reviews for meta-analyses that examine the association between gene-promoter methylation and cancer, published until January 2019 in English. We used AMSTAR to assess the quality of the included studies and applied a set of pre-specified criteria to evaluate the magnitude of each association. We provide a comprehensive overview of 80 unique combinations between 22 different genes and 18 cancer outcomes, all of which indicated a positive association between promoter hypermethylation and cancer. In total, the 70 meta-analyses produced significant results under a random-effects model with odds ratios that ranged from 1.94 to 26.60, with the summary effect being in favor of the unmethylated group in all cases. Three of the strong evidence associations involve RASSF1 methylation on bladder cancer risk (OR = 18.46; 95% CI: 12.69-26.85; I2 = 0%), MGMT methylation on NSCLC (OR = 4.25; 95% CI: 2.83-6.38; I2 = 22.4%) and RARB methylation on prostate cancer (OR = 6.87; 95% CI: 4.68-10.08; I2 = 0%). Meta-analyses showed a moderate quality, AMSTAR score ranging from 4 to 9 (Mdn = 8; IQR: 7.0 to 8.0). As primary studies and meta-analyses on the subject accumulate, more genetic loci may be found to be highly associated with specific cancer types and hence the biomarker sets will become wider.


Assuntos
Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Neoplasias/genética , Receptores do Ácido Retinoico/genética , Proteínas Supressoras de Tumor/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Masculino , Metanálise como Assunto , Razão de Chances , Regiões Promotoras Genéticas , Neoplasias da Próstata/genética , Neoplasias da Bexiga Urinária/genética
2.
Cytogenet Genome Res ; 158(1): 25-31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31055587

RESUMO

Diagnosing a complex genetic syndrome and correctly assigning the concomitant phenotypic traits to a well-defined clinical form is often a medical challenge. In this work, we report the analysis of a family with complex phenotypes, including microcephaly, intellectual disability, dysmorphic features, and polydactyly in the proband, with the aim of adding new aspects for obtaining a clear diagnosis. We performed array-comparative genomic hybridization and quantitative reverse transcriptase PCR (qRT-PCR) analyses. We identified a deletion of chromosome 20p12.1 involving the macrodomain containing 2/mono-ADP ribosylhydrolase 2 gene (MACROD2) in several members of the family. This gene is actually not associated with a specific syndrome but with congenital anomalies of multiple organs. qRT-PCR showed higher levels of a MACROD2 mRNA isoform in the individuals carrying the deletion. Our results, together with other data reported in the literature, support the hypothesis that the deletion in MACROD2 can affect correct embryonic development and that the presence of another associated event, such as epigenetic modifications at the MACROD2 locus, can influence the level of severity of the pathology.


Assuntos
Anormalidades Múltiplas/genética , Enzimas Reparadoras do DNA/genética , Hidrolases/genética , Deficiência Intelectual/genética , Rim/anormalidades , Microcefalia/genética , Pâncreas/anormalidades , Polidactilia/genética , Deleção de Sequência , Adulto , Cromossomos Humanos Par 20/genética , Cromossomos Humanos Par 20/ultraestrutura , Hibridização Genômica Comparativa , Enzimas Reparadoras do DNA/deficiência , Enzimas Reparadoras do DNA/fisiologia , Desenvolvimento Embrionário/genética , Feminino , Humanos , Hidrolases/deficiência , Hidrolases/fisiologia , Masculino , Linhagem , Fenótipo , Transtornos Psicomotores/genética
3.
Ecotoxicol Environ Saf ; 178: 168-177, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31004929

RESUMO

OBJECTIVES: Among the numerous agents, genetic factors and environmental elements such as pesticides have an important role in colorectal cancer (CRC) incidence. The present study aimed to investigate the probable-role of some organochlorine pesticides (OCPs) and organophosphorous pesticides (OPPs) in patients with CRC. METHODS: In this case-control study, 42 patients with CRC and 30 healthy subjects were selected. The serum levels of some OCPs (α-HCH, ß-HCH, γ-HCH, 2,4 DDE, 4,4 DDE, 2,4DDT and 4,4DDT) were measured by gas chromatography (GC) method. Serum levels of malondialdehyde (MDA), and total antioxidant capacity (TAC) as well as the enzyme activity of acetylcholinesterase (AChE) and arylesterase activity of Paraoxonase-1 (PON-1) were evaluated in all participants. The methylation specific PCR (MSP) assay was used for determining the methylation status of CpG island of p16 and MGMT genes in CRC patients. RESULTS: The mean serum levels of each OCPs were significantly higher in the patient group compared to the control group (P < 0.001). The AChE and arylesterase activity of PON-1 in the patient group were significantly lower than the control group (P < 0.001). The mean serum levels of MDA and TAC in the serum of the patient group were significantly higher than the control group (P < 0.001 and P < 0.002, respectively). The current findings demonstrated significantly hypermethylation of p16 promoter in CRC patients. CONCLUSION: Regarding the higher levels of OCPs in CRC patients, along with hypermethylation of the p16 promoter gene, diminishing in AChE and PON-1 activity and increasing in oxidative stress factors, the role of OCPs and OPPs in the CRC progression in the South-East of Iran may be assumed.


Assuntos
Neoplasias Colorretais/sangue , Hidrocarbonetos Clorados/sangue , Compostos Organofosforados/sangue , Praguicidas/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Ilhas de CpG , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Genes p16 , Humanos , Irã (Geográfico) , Masculino , Malondialdeído/análise , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética
4.
Zhonghua Bing Li Xue Za Zhi ; 48(3): 186-191, 2019 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-30831643

RESUMO

Objective: To investigate the prognostic impact of alterations of epidermal growth factor receptor(EGFR) and MGMT in glioblastoma. Methods: The retrospective study included 161 supratentorial glioblastomas diagnosed in the Department of Pathology, Xuanwu Hospital, Capital Medical University from 2009 to 2015. EGFR and EGFRvⅢ protein expression was detected by immunohistochemistry; EGFR amplification was detected by fluorescence in situ hybridization; MGMT promoter methylation was detected by pyrosequencing. The change of molecular genetics EGFR and MGMT and outcome were assessed statistically. Results: There were 161 patients, including 85 (52.8%) males and 76 (47.2%) females. The mean age was 53 years, and the median overall survival was 13 months. The integrated classification of glioblastoma included 16 IDH-mutant, 134 wild type, and 11 NOS. The rate of overexpression of EGFR protein was 32.9%(53/161), and that of EGFR amplification was 37.5%(18/48). There was high concordance between immunohistochemistry and FISH(85.4%, Kappa=0.475, P<0.01) and between the level of EGFR protein and EGFR amplification (P<0.01). Twelve cases showed EGFRvⅢ expression, and all also showed EGFR protein overexpression; 149 cases were EGFRv Ⅲ wild type, and EGFR protein overexpression was seen in 27.5%(41/149) of cases. There was no correlation between EGFR and EGFRv Ⅲ expression. Of all cases, 70.2%(106/151) showed MGMT promoter methylation by pyrosequencing. The changes of molecular genetics of EGFR and MGMT were not related. EGFR amplification and protein overexpression had no significant relationship with prognosis. Patients with EGFRv Ⅲ-mutant had shorter survival time than the EGFRv Ⅲ-wild type(P=0.014); patients with MGMT promoter methylation had better prognosis than without (PFS:P=0.002,OS:P=0.006),and MGMT promoter methylation was an independent predictor for overall survival (HR=0.269, 95%CI 0.124-0.583, P=0.001). Conclusions: EGFR protein expression by immunohistochemistry correlates with the status of EGFR amplification. Patients with EGFRv Ⅲ-mutant tumors have poorer prognosis than that with EGFRv Ⅲ-wild type tumors. MGMT promoter methylation is closely associated with prognosis and an independent predictor for overall survival.


Assuntos
Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Neoplasias Supratentoriais/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Biomarcadores Tumorais/metabolismo , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Receptores ErbB/genética , Feminino , Amplificação de Genes , Glioblastoma/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Metilação , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , Estudos Retrospectivos , Neoplasias Supratentoriais/genética , Proteínas Supressoras de Tumor/genética
5.
Dig Liver Dis ; 51(4): 595-599, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30824408

RESUMO

INTRODUCTION: Neuroendocrine tumors (NETs) are rare, but their incidence is rising. Alkylating agents (ALKY), temozolomide and streptozotocin, are the main chemotherapies used for advanced pancreatic NETs. According to retrospective data, O6-methylguanine-DNA methyltransferase (MGMT) status appears to be a predictive factor of the response to ALKY. AIMS: The main objective is to evaluate the value of tumor MGMT promoter (pMGMT) methylation in the prediction of the objective response (OR) at 3 months in patients treated with ALKY. Secondly, we will evaluate the value of MGMT immunohistochemistry and the efficacy of treatment with ALKY vs. oxaliplatin-based chemotherapy (Ox). MATERIALS AND METHODS: A national, prospective, open-label, randomized, controlled and multicenter trial was designed. Main inclusion criteria are: adult patients with well-differentiated advanced duodeno-pancreatic, lung, or unknown primitive NETs with a validated indication for chemotherapy. pMGMT methylation will be assessed by pyrosequencing, but an ancillary study will compare this technique with others ones including MGMT immunohistochemistry. RESULTS: A total of 104 patients will be randomly assigned (1:1 for unmethylated or 2:1 for methylated pMGMT NETs) to either the ALKY arm or to the Ox arm. CONCLUSION: Recruitment started on October 16, 2018 (NCT03217097) and will be open in 21 centers in France.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Ensaios Clínicos Fase II como Assunto , Metilação de DNA , Feminino , França , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Valor Preditivo dos Testes , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estreptozocina/uso terapêutico , Temozolomida/uso terapêutico , Resultado do Tratamento
6.
Int J Oncol ; 54(5): 1864-1874, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864696

RESUMO

Malignant melanoma is a highly aggressive skin cancer that is highly resistant to chemotherapy. Adjuvant therapy is administered to patients with melanoma that possess no microscopic metastases or have a high risk of developing microscopic metastases. Methylating agents, including dacarbazine (DTIC) and temozolomide (TMZ), pegylated interferon (IFN)­α2b and interleukin­2 have been approved for adjuvant immuno­chemotherapy; however, unsatisfactory results have been reported following the administration of methylating agents. IFN­ß has been considered to be a signaling molecule with an important therapeutic potential in cancer. The aim of the present study was to elucidate whether antitumor effects could be augmented by the combination of TMZ and IFN­ß in malignant melanoma. We evaluated the efficacy of TMZ and IFN­ß by comparing O6­methylguanine­DNA transferase (MGMT)­proficient and ­deficient cells, as MGMT has been reported to be associated with the resistance to methylating agents. Cell viability was determined by counting living cells with a Coulter counter, and apoptosis was analyzed by dual staining with Annexin V Alexa Fluor® 488 and propidium iodide. The expression of proteins involved in the cell cycle, apoptosis and autophagy was evaluated by western blot analysis. The combined treatment with TMZ and IFN­ß suppressed cell proliferation and induced cell cycle arrest. We also demonstrated that a combination of TMZ and IFN­ß enhanced apoptosis and autophagy more efficiently compared with TMZ treatment alone. These findings suggest that antitumor activity may be potentiated by IFN­ß in combination with TMZ.


Assuntos
Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Interferon beta/farmacologia , Melanoma/genética , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/genética , Autofagia , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo
7.
Clin Chim Acta ; 494: 64-70, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30871974

RESUMO

BACKGROUND: A consanguineous Chinese family was affected by an apparently novel autosomal recessive disorder characterized by cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability. METHODS: The family was evaluated by homozygosity mapping, haplotype analysis, whole exome sequencing, and candidate gene mutation screening to identify the disease-associated gene and mutation. Bioinformatics methods were used to predict the functional significance of the mutated gene product. ERCC8 mutations and phenotypes were examined. RESULTS: All three patients presented cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability. Whole genome and candidate region linkage analysis in the consanguineous family revealed a maximum logarithm of the odds score at 5q12.1. This homozygous region was confirmed by homozygosity mapping. The pathogenic missense mutation p.Gly257Arg affecting an evolutionary highly conserved amino acid was identified in ERCC8 at 5q12.1. Integrated application of whole exome sequencing and homozygosity mapping is an efficient approach for gene mapping and mutation identification in consanguineous families. CONCLUSIONS: We identified a novel ERCC8 mutation and new unique disease phenotype. These results also confirmed the genotype-phenotype relationship between mutations in ERCC8 and clinical findings.


Assuntos
Ataxia Cerebelar/genética , Mapeamento Cromossômico , Consanguinidade , Enzimas Reparadoras do DNA/genética , Mutação , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma , China , Feminino , Genótipo , Humanos , Masculino , Linhagem , Fenótipo
8.
BMC Med Genet ; 20(1): 45, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898087

RESUMO

BACKGROUND: DNA double-strand breaks (DSBs) are among the most deleterious types of DNA damage. DSBs are repaired by homologous recombination or non-homologous end-joining (NHEJ). NHEJ, which is central to the process of V(D)J recombination is the principle pathway for DSB repair in higher eukaryotes. Mutations in NHEJ1 gene have been associated with severe combined immunodeficiency. CASE PRESENTATION: The patient was a 3.5-year-old girl, a product of consanguineous first-degree cousin marriage, who was homozygous for a nonsense mutation in NHEJ1 gene. She had initially presented with failure to thrive, proportional microcephaly as well as autoimmune hemolytic anemia (AIHA), which responded well to treatment with prednisolone. However, the patient was immunocompetent despite having this pathogenic mutation. CONCLUSIONS: Herein, we report on a patient who was clinically immunocompetent despite having a pathogenic mutation in NHEJ1 gene. Our findings provided evidence for the importance of other end-joining auxiliary pathways that would function in maintaining genetic stability. Clinicians should therefore be aware that pathogenic mutations in NHEJ pathway are not necessarily associated with clinical immunodeficiency.


Assuntos
Códon sem Sentido , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Imunocompetência , Pré-Escolar , Consanguinidade , Feminino , Humanos , Mutação
9.
Tumour Biol ; 41(3): 1010428319830837, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30880589

RESUMO

The polymorphisms of invasion suppressor gene CDH1 and DNA mismatch repair gene Exo1 have been reported to play critical role in the development, tumorigenesis, and progression of several kinds of cancers including prostate cancer. This study was designed to analyze the contribution of single-nucleotide polymorphisms of the CDH1 (-160C/A) and Exo1 (K589E) to prostate cancer susceptibility in Bangladeshi population. The study included 100 prostate cancer cases and age-matched 100 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to determine the genetic polymorphisms. A significant association was found between CDH1 -160C/A (rs16260) and Exo1 (rs1047840, K589E) polymorphisms and prostate cancer risk. In case of CDH1 -160C/A polymorphism, the frequencies of the three genotypes C/C,C/A, and A/A were 45%, 48%, and 7% in cases and 63%, 32%, and 5% in controls, respectively. The heterozygote C/A genotype and combined C/A + A/A genotypes showed 2.10-fold (odds ratio = 2.1000, 95% confidence interval = 1.2956-4.0905, p = 0.013) and 2.08-fold (odds ratio = 2.0811, 95% confidence interval = 1.1820-3.6641, p = 0.011) increased risk of prostate cancer, respectively, when compared with homozygous C/C genotypes. The variant A allele also was associated with increased risk of prostate cancer (odds ratio = 1.6901, 95% confidence interval = 1.0740-2.6597, p = 0.0233). In case of Exo1 (K589E) polymorphism, G/A heterozygote, A/A homozygote, and combined G/A + A/A genotypes were found to be associated with 2.30-, 4.85-, and 3.04-fold higher risk of prostate cancer, respectively (odds ratio = 2.3021, 95% confidence interval = 2.956-4.0905, p = 0.0031; odds ratio = 4.8462, 95% confidence interval = 1.0198-23.0284, p = 0.0291; OR = 3.0362, 95% confidence interval = 1.7054-5.4053, p = 0.0001, respectively). The "A" allele showed significant association with increased susceptibility (2.29-fold) to prostate cancer (odds ratio = 2.2955, 95% confidence interval = 1.4529-3.6270, p = 0.0004). Our results suggest that CDH1 -160C/A and Exo1 K589E polymorphisms are associated with increased susceptibility to prostate cancer in Bangladeshi population.


Assuntos
Antígenos CD/genética , Caderinas/genética , Enzimas Reparadoras do DNA/genética , Grupos Étnicos/genética , Exodesoxirribonucleases/genética , Predisposição Genética para Doença/genética , Polimorfismo de Fragmento de Restrição/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Idoso , Alelos , Bangladesh , Estudos de Casos e Controles , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
10.
Doc Ophthalmol ; 138(3): 241-246, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30820731

RESUMO

PURPOSE: Cockayne syndrome is a rare autosomal recessive disease, also known as a progeria disorder, causing dwarfism, senile appearance and multiple systemic affections. Ophthalmic abnormalities are frequent, for example, in the forms of pigmentary retinopathy with low visual acuity. We present two genetic-confirmed cases with a detailed electrophysiological exploration of their retinal findings. METHODS: Complete ophthalmic exploration is undertaken, including full-field electroretinogram under ISCEV guidelines and multifocal electroretinogram (RETI-scan science, Roland-Consult, Germany), ultra-wide-field retinography and autofluorescence (Optomap, Optos PLC, Dunfermline, Scotland, UK) and macular and retinal nerve fibre layer optical coherence tomography (Cirrus, Carl-Zeiss Meditec, Inc, Dublin, CA). RESULTS: Both cases presented with CSA/ERCC8 mutation and low visual acuity. Diffuse pigmentary retinopathy with macular atrophy was found in ultra-wide-field retinography and autofluorescence. Electrophysiological testing reported wide retinal dysfunction on both cone and rod system with macular involvement. CONCLUSIONS: Pigmentary retinopathy in CS could translate a wide dysfunction of the retina with major affection of external retinal layers of both cone and rod cells. Macular implication is also present and could explain progressive vision loss in such cases.


Assuntos
Síndrome de Cockayne/fisiopatologia , Retina/fisiopatologia , Retinite Pigmentosa/fisiopatologia , Adulto , Síndrome de Cockayne/genética , Enzimas Reparadoras do DNA/genética , Técnicas de Diagnóstico Oftalmológico , Eletrorretinografia/métodos , Feminino , Humanos , Masculino , Mutação , Tomografia de Coerência Óptica/métodos , Fatores de Transcrição/genética , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia
11.
Bull Cancer ; 106(2): 119-128, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30713006

RESUMO

Microsatellite instability (MSI), which is caused by deficiency of the DNA mismatch repair (MMR) system, is the molecular abnormality observed in tumors associated with Lynch syndrome. Lynch syndrome represents one of the most frequent conditions of cancer predisposition in human, thus requiring specific care and genetic counseling. Moreover, research has recently focused increasingly on MMR deficiency due to its positive predictive value for the efficacy of immune checkpoints inhibitors (ICKi) in metastatic tumors, regardless of their primary origin. MSI has also been demonstrated to constitute an independent prognostic factor in several tumor types, being also associated with alternative response to chemotherapy. These observations have led many professional medical organizations to recommend universal screening of all newly diagnosed colorectal cancers for dMMR/MSI status and increasing evidence support the evaluation of MSI in all human tumors regardless of the cancer tissue of origin. Currently, two standard reference methods, namely immunohistochemistry and polymerase chain reaction, are recommended for the detection of dMMR/MSI status. These methods are equally valid as the initial screening test for dMMR/MSI in colorectal cancer. To date, there is no recommendation for the detection of dMMR/MSI in other primary tumors. In this review, we will present a comprehensive overview of the methods used for evaluation of tumor dMMR/MSI status in colorectal cancer, as well as in other tumor sites. We will see that the evaluation of this status remains challenging in some clinical settings, with the need to improve the above methods in these specific contexts.


Assuntos
Neoplasias Colorretais/diagnóstico , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Algoritmos , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Enzimas Reparadoras do DNA/genética , Humanos , Imuno-Histoquímica , Programas de Rastreamento , Reação em Cadeia da Polimerase
12.
BMC Cancer ; 19(1): 108, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30700254

RESUMO

BACKGROUND: Malignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term "BRCAness". An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis. METHODS: We investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members. RESULTS: A BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM. CONCLUSIONS: Defects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients' clinical management and outcome.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/genética , Mesotelioma/genética , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Reparo de DNA por Recombinação/genética , Apoptose/efeitos dos fármacos , Aurora Quinase A/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Recombinação Homóloga/genética , Humanos , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Pemetrexede/farmacologia
13.
Nucleic Acids Res ; 47(7): 3784-3794, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30753618

RESUMO

Cockayne syndrome group B (CSB, also known as ERCC6) protein is involved in many DNA repair processes and essential for transcription-coupled repair (TCR). The central region of CSB has the helicase motif, whereas the C-terminal region contains important regulatory elements for repair of UV- and oxidative stress-induced damages and double-strand breaks (DSBs). A previous study suggested that a small part (∼30 residues) within this region was responsible for binding to ubiquitin (Ub). Here, we show that the Ub-binding of CSB requires a larger part of CSB, which was previously identified as a winged-helix domain (WHD) and is involved in the recruitment of CSB to DSBs. We also present the crystal structure of CSB WHD in complex with Ub. CSB WHD folds as a single globular domain, defining a class of Ub-binding domains (UBDs) different from 23 UBD classes identified so far. The second α-helix and C-terminal extremity of CSB WHD interact with Ub. Together with structure-guided mutational analysis, we identified the residues critical for the binding to Ub. CSB mutants defective in the Ub binding reduced repair of UV-induced damage. This study supports the notion that DSB repair and TCR may be associated with the Ub-binding of CSB.


Assuntos
Quebras de DNA de Cadeia Dupla , DNA Helicases/química , Enzimas Reparadoras do DNA/química , Proteínas de Ligação a Poli-ADP-Ribose/química , Ubiquitina/química , Ubiquitinas/química , Fatores de Transcrição Winged-Helix/química , Sequência de Aminoácidos/genética , Sobrevivência Celular , Síndrome de Cockayne/genética , Síndrome de Cockayne/metabolismo , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , DNA Helicases/genética , Reparo do DNA/genética , Reparo do DNA/efeitos da radiação , Enzimas Reparadoras do DNA/genética , Humanos , Mutação , Proteínas de Ligação a Poli-ADP-Ribose/genética , Conformação Proteica em alfa-Hélice/genética , Ubiquitina/genética , Ubiquitinas/genética , Raios Ultravioleta , Fatores de Transcrição Winged-Helix/genética
14.
Genome Res ; 29(3): 439-448, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718334

RESUMO

The homologous recombination repair (HRR) pathway repairs DNA double-strand breaks in an error-free manner. Mutations in HRR genes can result in increased mutation rate and genomic rearrangements, and are associated with numerous genetic disorders and cancer. Despite intensive research, the HRR pathway is not yet fully mapped. Phylogenetic profiling analysis, which detects functional linkage between genes using coevolution, is a powerful approach to identify factors in many pathways. Nevertheless, phylogenetic profiling has limited predictive power when analyzing pathways with complex evolutionary dynamics such as the HRR. To map novel HRR genes systematically, we developed clade phylogenetic profiling (CladePP). CladePP detects local coevolution across hundreds of genomes and points to the evolutionary scale (e.g., mammals, vertebrates, animals, plants) at which coevolution occurred. We found that multiscale coevolution analysis is significantly more biologically relevant and sensitive to detect gene function. By using CladePP, we identified dozens of unrecognized genes that coevolved with the HRR pathway, either globally across all eukaryotes or locally in different clades. We validated eight genes in functional biological assays to have a role in DNA repair at both the cellular and organismal levels. These genes are expected to play a role in the HRR pathway and might lead to a better understanding of missing heredity in HRR-associated cancers (e.g., heredity breast and ovarian cancer). Our platform presents an innovative approach to predict gene function, identify novel factors related to different diseases and pathways, and characterize gene evolution.


Assuntos
Evolução Molecular , Reparo de DNA por Recombinação , Software , Animais , Enzimas Reparadoras do DNA/genética , Loci Gênicos , Filogenia , Plantas/genética
15.
Pathol Res Pract ; 215(5): 885-892, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30723053

RESUMO

Genetic and epigenetic alterations importantly contribute to the pathogenesis of lung cancer. In the study, we measured the frequency and distribution of molecular abnormalities of EGFR as well as the aberrant promoter methylations of BRCA1, MGMT, MLH1, and RASSF1A in Vietnamese lung adenocarcinomas. We investigated the association between genetic and epigenetic alteration, and between each abnormality with clinicopathologic parameters. Somatic EGFR mutation that was found in 49/139 (35.3%) lung adenocarcinomas showed a significant association with young age, female gender, and non-smokers. EGFR overexpression was identified in 82 tumors (59.0%) and statistical relationships with EGFR or BRCA1 methylation but not EGFR mutation. In addition, EGFR, BRCA1, MGMT, MLH1, and RASSF1A methylations were found in 33 (23.7%), 41 (29.5%), 46 (33.1%), 28 (20.1%), and 41 (29.5%) cases of a total of 139 lung adenocarcinomas, respectively. The RASSF1A methylation was found to be linked to the smoking habit. Methylations in MGMT and RASSF1A were also found to correlate with metastasis status. Furthermore, the distribution of EGFR mutation and that of BRCA1, MGMT or RASSF1A methylation were significantly exclusive in lung adenocarcinomas. The main finding of our study demonstrate that epigenetic abnormalities might play a critical role for the lung tumorigenesis in patients with smoking history and metastasis, and partly affect the predictive value of EGFR mutations through blocking expression due to promoter EGFR hypermethylation. Mutually exclusive distribution of genetic and epigenetic alterations reflects differently biological characteristics in the etiology of lung adenocarcinomas.


Assuntos
Adenocarcinoma de Pulmão/genética , Metilação de DNA/genética , Epigênese Genética/genética , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Proteína BRCA1/genética , Biomarcadores Tumorais/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Proteínas Supressoras de Tumor/genética
16.
J Neurooncol ; 142(3): 529-536, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30790133

RESUMO

PURPOSE: The aim of this study is to investigate the association between postoperative tumor volume and overall survival (OS) of O6-methylguanine DNA methyltransferase (MGMT)-unmethylated glioblastoma patients. METHODS: One hundred-twenty-six patients with MGMT-unmethylated glioblastoma who were treated either with surgical resection or needle biopsy between 2006 and 2015 were included in this retrospective cohort. Pre- and postcontrast T1 weighted images were evaluated in order to determine pre- and postoperative contrast-enhancing tumor volumes (CE-TV). Cox regression models adjusted for other significant prognostic factors were used to investigate the association between postoperative tumor volume and survival. RESULTS: Complete resection of CE-TV was significantly associated with longer OS in the univariate analysis (HR 0.61; 95% CI 0.40-0.94; p = 0.02). However, this fact could not be confirmed after adjusting the model for other relevant prognostic factors (HR 1.01; 95% CI 0.65-1.55; p = 0.962). Postoperative CE-TV was significantly associated with survival in both univariate (HR: 1.04; 95% CI 1.025-1.055; p < 0.001) and multivariate analyses (HR: 1.027; 95% CI 1.005-1.049; p = 0.014). CONCLUSIONS: Although complete resection of tumor tissue was not significantly associated with longer OS in MGMT-unmethylated GBM patients, maximum safe resection should always be attempted, since postoperative tumor volume is strongly associated with OS.


Assuntos
Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/mortalidade , Glioblastoma/patologia , Neurocirurgia/métodos , Complicações Pós-Operatórias , Proteínas Supressoras de Tumor/genética , Feminino , Seguimentos , Glioblastoma/genética , Glioblastoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
17.
Proc Natl Acad Sci U S A ; 116(8): 2961-2966, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30718431

RESUMO

Chemoresistance is a severe outcome among patients with ovarian cancer that leads to a poor prognosis. MCL1 is an antiapoptotic member of the BCL-2 family that has been found to play an essential role in advancing chemoresistance and could be a promising target for the treatment of ovarian cancer. Here, we found that deubiquitinating enzyme 3 (DUB3) interacts with and deubiquitinates MCL1 in the cytoplasm of ovarian cancer cells, which protects MCL1 from degradation. Furthermore, we identified that O6-methylguanine-DNA methyltransferase (MGMT) is a key activator of DUB3 transcription, and that the MGMT inhibitor PaTrin-2 effectively suppresses ovarian cancer cells with elevated MGMT-DUB3-MCL1 expression both in vitro and in vivo. Most interestingly, we found that histone deacetylase inhibitors (HDACis) could significantly activate MGMT/DUB3 expression; the combined administration of HDACis and PaTrin-2 led to the ideal therapeutic effect. Altogether, our results revealed the essential role of the MGMT-DUB3-MCL1 axis in the chemoresistance of ovarian cancer and identified that a combined treatment with HDACis and PaTrin-2 is an effective method for overcoming chemoresistance in ovarian cancer.


Assuntos
Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Endopeptidases/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Supressoras de Tumor/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Transdução de Sinais/efeitos dos fármacos
18.
Int J Mol Sci ; 20(4)2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30769804

RESUMO

The MRE11-RAD50-NBS1 (MRN) complex has been studied in multiple cancers. The identification of MRN complex mutations in mismatch repair (MMR)-defective cancers has sparked interest in its role in colorectal cancer (CRC). To date, there is evidence indicating a relationship of MRN expression with reduced progression-free survival, although the significance of the MRN complex in the clinical setting remains controversial. In this review, we present an overview of the function of the MRN complex, its role in cancer progression, and current evidence in colorectal cancer. The evidence indicates that the MRN complex has potential utilisation as a biomarker and as a putative treatment target to improve outcomes of colorectal cancer.


Assuntos
Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Proteína Homóloga a MRE11/genética , Proteínas Nucleares/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Complexos Multiproteicos/genética , Prognóstico
20.
Acta Oncol ; 58(3): 334-341, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30732527

RESUMO

BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor with a short overall survival (OS) in general. The treatment of GBM has evolved over the last decades and is today multimodal including surgical resection followed by radiochemotherapy and adjuvant chemotherapy for patients in good performance status. The aim of this study was to evaluate the development of treatment and the outcome for GBM patients at a single regional center. PATIENTS AND METHODS: Survival was studied for 571 patients in our region diagnosed with GBM between 1995 and 2015. Samples from 244 patients out of those treated 2005-2015 have been included in a tissue/blood bank and a clinical database has been set up with basic patient characteristics and details on surgery and non-surgical treatment. RESULTS: The median OS for all patients from 1995 to 2015 was 9.3 months. There was a stepwise improvement from 6.9 to 10.3 months for patients diagnosed 1995-1996 and 2010-2015, respectively (p < .05). The 2-year survival for the same time periods improved from 7% to 18% (p < .01). After introduction of postoperative radiochemotherapy for patients in good performance status in 2005 an increased OS was noted and following implementation of intraoperative 5-aminolevulinic acid the number of tumor resection ≥95% did increase from 33% to 54% (p < .001). Positive prognostic factors for survival were young age, good performance status, absence of inflammatory disease, absence of diabetes or metabolic disease, tumor resection ≥95%, and completion of postoperative radiochemotherapy. DISCUSSION: The results of this study are consistent with earlier results regarding survival and prognostic factors and confirm results from randomized controlled trials in a clinical setting. Despite the improvements made, the prognosis is still dismal and the need for further research on GBM treatment is great.


Assuntos
Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/genética , Glioblastoma/terapia , Hospitais Universitários/estatística & dados numéricos , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Suécia/epidemiologia , Proteínas Supressoras de Tumor/genética
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