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1.
Arch Oral Biol ; 110: 104627, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31862643

RESUMO

OBJECTIVE: To evaluate the immunoexpression of DNA base excision repair (BER) [apurinic/apyrimidinic endonuclease 1 (APE-1), X-ray repair cross complementing 1 (XRCC-1)] and nucleotide excision repair (NER) [xeroderma pigmentosum complementation group (XPF)] proteins in benign epithelial odontogenic lesions with different biological behaviors. DESIGN: Thirty solid ameloblastomas, 30 non-syndromic odontogenic keratocysts (NSOKCs), 29 syndromic odontogenic keratocysts (SKOCs), 30 dentigerous cysts (DCs) and 20 dental follicles (DFs) were evaluated quantitatively for APE-1, XRCC-1 and XPF through immunohistochemistry. RESULTS: Nuclear expression of APE-1 was significantly higher in NSOKCs, SOKCs, and ameloblastomas in comparison to DCs (p < 0.001). Nuclear expression of XRCC-1 was higher in NSOKCs and SOKCs than in DCs (p < 0.05). At the nuclear level, XPF expression was higher in NSOKCs and SOKCs than in DCs and ameloblastomas (p < 0.05). A statistically significant higher expression of APE-1 (nuclear), XRCC-1 (nuclear), and XPF (nuclear and cytoplasmic) was found in all odontogenic lesion samples as compared to DFs (p < 0.05). For all lesions, there was a positive correlation between nuclear expression of APE-1 and XRCC-1 or XPF (p < 0.05). CONCLUSIONS: Our results suggest a potential involvement of APE-1, XRCC-1 and XPF proteins in the pathogenesis of benign epithelial odontogenic lesions, especially in those with more aggressive biological behavior, such as ameloblastomas, NSOKCs, and SOKCs. We also showed that the expression of APE-1 was positively correlated with the nuclear expression of XRCC-1 and XPF, which may suggest an interaction between the BER and NER pathways in all odontogenic lesions studied herein.


Assuntos
Ameloblastoma , Reparo do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Proteínas de Ligação a DNA , Cisto Dentígero , Cistos Odontogênicos , Proteína 1 Complementadora Cruzada de Reparo de Raio-X , Ameloblastoma/genética , DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Proteínas de Ligação a DNA/metabolismo , Cisto Dentígero/genética , Expressão Gênica , Humanos , Cistos Odontogênicos/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo
2.
Asian Pac J Cancer Prev ; 20(8): 2345-2351, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450905

RESUMO

Background: Glioma, most common primary malignant brain tumor in adults, is highly aggressive and associated with a poor prognosis. Evaluate the association of polymorphisms related of to the cell cycle, integrity and DNA repair with gliomas, as well as lifestyle habits, comorbidities, survival and response to treatment. Methods: Were studied 303 individuals distributed into: Study Group - 100 patients with gliomas, regardless of the degree of malignancy, and Control Group - 203 individuals without clinical signs of the disease. These polymorphisms were genotyped by TaqMan® SNP Genotyping Assay. Significance level was set at 5%. Results: Smoking, alcohol consumption, systemic arterial hypertension (SAH) and diabetes mellitus (DM) prevailed in patients, compared to controls (P=0.0088, P=0.0001, P=0.0001, P=0.0011, respectively). In the logistic regression analysis, alcohol consumption and SAH were identified as independent risk factors for gliomas (P=0.0001, P=0.0027, respectively). Patients with low-grade gliomas showed survival in one year (92.0±6.8%), compared to patients with high-grade gliomas (24.0±5.3; P=0.011). Conclusion: Polymorphisms involved in cell cycle, telomere protection and stability and DNA repair are not associated with gliomas. On the other hand, alcohol consumption and SAH stand out as independent risk factors for the disease. Low-grade gliomas, response to treatment and the combination of chemotherapy with Temozolomide and radiation therapy show increased survival of patients.


Assuntos
Biomarcadores Tumorais/genética , Ciclina D1/genética , DNA Helicases/genética , Glioma/genética , Glioma/patologia , Polimorfismo Genético , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Taxa de Sobrevida , Telômero/química , Telômero/genética , Adulto Jovem
3.
Toxicol Lett ; 316: 20-26, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31465813

RESUMO

Health-care personnel handling antineoplastic drugs could be at risk for adverse health effects. We aimed to evaluate genotoxic and cytotoxic effects of antineoplastic drug exposure of personnel preparing and administering such drugs in three Oncology Hospitals in Italy enrolling 42 exposed subjects and 53 controls. Furthermore, we aimed to study the possible influence of XRCC1 and hOGG1 DNA repair genes polymorphisms on genotoxicity induced on buccal cells. We performed workplace and personal monitoring of some drugs and used exposure diary informations to characterize the exposure. Urinary 5-FU metabolite (α-fluoro-ß-alanine) was measured. Buccal Micronucleus Cytome (BMCyt) assay was used to evaluate DNA damage and other cellular anomalies. GEM and 5-FU contamination was found in 68% and 42% of wipe/swab samples respectively. GEM deposition was found on workers' pads while no α-fluoro-ß-alanine was found. BMCyt-assay showed higher genotoxicity and cytotoxicity on nurses administering antineoplastics than on preparators and controls. Among micronucleus (MN) positive (with MN frequency higher than 1.5‰) exposed subjects, the percentage of those carrying XRCC1 mut/het genotype was higher than in MN positive-controls. Using the sensitive BMCyt assay, we demonstrated that handling antineoplastics still represents a potential occupational health risk for workers that should be better trained/informed regarding such risks.


Assuntos
Antineoplásicos/efeitos adversos , Desoxicitidina/análogos & derivados , Monitoramento Ambiental/métodos , Fluoruracila/efeitos adversos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , Mucosa Bucal/efeitos dos fármacos , Recursos Humanos de Enfermagem no Hospital , Exposição Ocupacional/efeitos adversos , Saúde do Trabalhador , Enfermagem Oncológica , Adulto , Antineoplásicos/urina , Biomarcadores/urina , Estudos de Casos e Controles , DNA Glicosilases/genética , Desoxicitidina/efeitos adversos , Desoxicitidina/urina , Feminino , Fluoruracila/urina , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/metabolismo , Exposição Ocupacional/prevenção & controle , Polimorfismo Genético , Medição de Risco , Fatores de Risco , Urinálise , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética
4.
Medicine (Baltimore) ; 98(32): e16541, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393355

RESUMO

BACKGROUNDS: Previous investigations yielded inconsistent results for the associations between pancreatic cancer (PC) risk and genetic polymorphisms. The study aimed to perform a systematic review and meta-analysis of studies exploring association of some genetic polymorphisms and PC risk. METHODS: We systematically searched on PubMed and Web of Science for association of genetic polymorphisms and PC risk published from 1969 to January 2019. We computed the multivariate odd ratio (OR) and 95% confidence intervals (CI), comparing different genetic types. RESULTS: The present meta-analysis showed significant associations between deoxyribonucleic acid (DNA) repair gene (X-ray repair cross-complementing group 1 (XRCC1) Arg399GIn and Arg194Trp, excision repair cross complementation 1 (ERCC1) rs11615 and rs3212986, ERCC2 rs13181) polymorphisms and PC risk. CONCLUSIONS: Because of the limited sample size and ethnicity enrolled in the present meta-analysis, further larger scaled studies should be performed to demonstrate the association.


Assuntos
Neoplasias Pancreáticas/genética , DNA Glicosilases/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética
5.
Int J Occup Environ Med ; 10(3): 124-136, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31325295

RESUMO

BACKGROUND: Coke oven workers are exposed to polycyclic aromatic hydrocarbons (PAHs) with possible genotoxicity and carcinogenicity. Metabolizing enzymes genes and DNA repair genes are suspected to be correlated with the level of DNA damage. They may contribute to variable individual sensitivity to DNA damage induced by PAHs exposure at workplace. OBJECTIVE: To investigate the relationship between biomarkers of PAHs: 1-hydroxypyrene (1-OHP), DNA adducts, and 8-hydroxy-2-deoxyguanosine (8-OHdG) in coke oven workers, and to assess the role of cytochrome P2E1 (CYP2E1) gene expression and DNA repairing gene (XRCC1) polymorphism in detecting workers at risk. METHODS: 85 exposed workers and 85 unexposed controls were enrolled into this study. Urinary 1-OHP, 8-OHdG, and BPDE-DNA adduct were measured. CYP2E1 gene expression and genotyping of XRCC1 399 Arg/Gln were evaluated by real-time PCR. RESULTS: The median urinary 1-OHP levels (6.3 µmol/mol creatinine), urinary 8-OHdG (7.9 ng/mg creatinine), DNA adducts (6.7 ng/µg DNA) in the exposed group were significantly higher than those in the unexposed group. Carriers of the variant allele (Gln) of XRCC1 had the highest levels of 1-OHP, DNA adducts and 8-OHdG, and the lowest level of CYP2E1 gene expression. In exposed workers, significant positive correlations were found between 1-OHP level and each of the work duration, 8-OHdG, and DNA adducts levels. There was a significant negative correlation between 1-OHP level and CYP2E1 gene expression. Work duration and CYP2E1 gene expression were predictors of DNA adducts level; 1-OHP level and work duration were predictors of urinary 8-OHdG level. CONCLUSION: Workers with higher exposure to PAH were more prone to oxidative DNA damage and cancer development. DNA adducts level reflects the balance between their production by CYP2E1 and elimination by XRCC1 gene.


Assuntos
Citocromo P-450 CYP2E1/genética , Adutos de DNA/genética , Desoxiguanosina/análogos & derivados , Monitoramento Ambiental/métodos , Exposição Ocupacional/análise , Pirenos/urina , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido , Adulto , Biomarcadores/urina , Coque , Citocromo P-450 CYP2E1/biossíntese , Adutos de DNA/urina , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/genética , Desoxiguanosina/urina , Egito , Humanos , Masculino , Pessoa de Meia-Idade , Hidrocarbonetos Policíclicos Aromáticos/urina , Polimorfismo Genético , Medição de Risco , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/biossíntese , Adulto Jovem
6.
Wiad Lek ; 72(5 cz 1): 784-789, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31175773

RESUMO

OBJECTIVE: Introduction: The frequency of alleles and genotypes of DNA repair genes in people working due to the influence of industrial aerosols (miners and workers of asbestos-cement plants (n = 215)) was studied. The aim of the work was to identify allelic polymorphisms affecting the formation of resistance or leading to an increased risk of developing bronchopulmonary pathology. PATIENTS AND METHODS: Materials and methods: In 90 patients with bronchopulmonary pathology and 125 persons working under the same conditions but without respiratory system diseases, the polymerase chain reaction in real time was determined by the polymorphisms of DNA repair genes: XPD (rs13181, rs799793), ERCC1 (rs11615), XRCC1 ( rs25487) and XRCC3 (rs861539), ATM (rs664677), XRCC7 (rs7003908) and MLH1 (rs1799977). RESULTS: Results: In the course of this study the alleles and genotypes contributing to resistance to the development of respiratory system pathologies were determined: XRCC1•G/A (rs25487) (OR=0.57; 95% CI: 0.32-1.02; P≤0.040; Χ²=4.14); MLH1•A (rs1799977) (OR=0.62; 95% CI: 0.40-0.96; P≤0.020; Χ²=5.06); MLH1•A/A (rs1799977) (OR=0.43; 95% CI: 0.24-0.79; P≤0.003; Χ²=8.73). Also, we established the alleles and genotypes associated with the risk of developing bronchopulmonary pathology: XPD•C/C (rs13181) (OR=2.20, 95% CI: 1.02-4.77; P≤0.020; Χ²=4.85); XRCC1•A/A (rs25487) (OR=3.37; 95 % CI: 1.22-9.63; P≤0.008; Χ²=6.94); ATM•T/T (rs664677) (OR=2.48; 95% CI: 1.16-5.31; Р≤0.010; Χ²=6.61); MLH1•G (rs1799977) (OR=1.61; 95% CI: 1.04-2.49; P≤0.020; Χ²=5.06); MLH1•A/G (rs1799977) (OR=2.32; 95% CI: 1.29-4.21; P≤0.002; Χ²=9.01). CONCLUSION: Conclusions: The results indicate the influence of allelic polymorphisms of DNA repair genes on the formation of resistance to the development of bronchopulmonary pathology under the action of industrial aerosols and open up prospects for the development of modern preventive measures.


Assuntos
Reparo do DNA , Predisposição Genética para Doença , Aerossóis , Alelos , Estudos de Casos e Controles , Proteínas de Ligação a DNA , Endonucleases , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
7.
Free Radic Res ; 53(5): 473-485, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31117842

RESUMO

Gallbladder cancer (GBC) is a fatal condition with dismal prognosis and aggressive local invasiveness; and with uncharacterised molecular pathology relating to non-specific therapeutic modalities. Given the importance of oxidative stress in chronic diseases and carcinogenesis, and the lacunae in literature regarding its role in gallbladder diseases, this study aimed to study the involvement of oxidative stress and deregulation in the base excision repair (BER) pathway in the pathogenesis of gallbladder diseases including GBC. This study involved patients from the North-East Indian population, where the numbers of reported cases are increasing rapidly and alarmingly. Oxidative stress, based on 8-OH-dG levels, was found to be significantly higher in gallbladder anomalies (cholelithiasis [CL] and cholecystitis [CS]) and GBC at the plasma and DNA level, and was associated with GBC severity. The expressions of key BER pathway genes were downregulated in gallbladder anomalies and GBC compared to controls, and in GBC compared to both non-neoplastic controls and gallbladder anomalies. Expression of XRCC1 and hOGG1 was significantly associated with both susceptibility and severity of GBC. The XRCC1 codon280 polymorphism was associated with disease susceptibility; and significantly higher oxidative stress was observed in hOGG1 genotypic variants. The genomes of GBC patients were found to be more hypermethylated compared to controls, with the promoters of XRCC1 and hOGG1 being hypermethylated and, therefore, being silenced. This study underlined the prognostic significance of the oxidative stress marker 8-OH-dG and BER pathway genes, especially hOGG1 and XRCC1, in gallbladder anomalies and GBC, as well as stated their potential for therapeutic targeting.


Assuntos
Colecistite/genética , Colelitíase/genética , DNA Glicosilases/genética , Reparo do DNA , Neoplasias da Vesícula Biliar/genética , Regulação Neoplásica da Expressão Gênica , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , /metabolismo , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Colecistite/complicações , Colecistite/patologia , Colecistite/cirurgia , Colelitíase/complicações , Colelitíase/patologia , Colelitíase/cirurgia , DNA Glicosilases/metabolismo , Metilação de DNA , Feminino , Vesícula Biliar/metabolismo , Vesícula Biliar/patologia , Vesícula Biliar/cirurgia , Neoplasias da Vesícula Biliar/complicações , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Predisposição Genética para Doença , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estresse Oxidativo/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Regiões Promotoras Genéticas , Índice de Gravidade de Doença , Transdução de Sinais , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo
8.
Turk J Gastroenterol ; 30(6): 517-523, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31144657

RESUMO

BACKGROUND/AIMS: Gastric cancers vary across countries and ethnic groups. They are the second most common type of cancer worldwide. Dietary and non-dietary factors as well as genetic and epigenetic alterations of many mechanisms are implicated in the development of gastric cancer. We aimed to determine the sequence of possible nucleotide changes, polymorphisms, and mutations, and to establish genotype and phenotype relation by performing whole DNA sequence analysis of the XRCC1 and ERCC1 genes belonging to base excision repair (BER) and nucleotide excision repair (NER) family of DNA repair genes in patients with gastric cancer. MATERIALS AND METHODS: We included 50 patients of both sexes who had received diagnosis of gastric cancer and 50 healthy people who showed same demographic traits that forms the control group. We analyzed the ERCC1 and XRCC1 genes by DNA sequence analysis on both groups. After the analysis, we compared the genotype-phenotype relation. RESULTS: Neither patients nor the control group has any nucleotide replacement in any exon of ERCC1 genes. We could not detect significant difference between patients and healthy groups when we correlated genotype contribution of mutations Arg194Trp, Arg208His, Arg399Gln detected in the XRCC1 gene and allele frequency. CONCLUSION: According to our study, the ERCC1 gene in Turkish population is not getting mutation in patients with gastric cancer and healthy individuals. Three mutations were detected in the XRCC1 gene, and these mutations were not associated with gastric cancer.


Assuntos
Proteínas de Ligação a DNA/genética , Endonucleases/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Gástricas/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Reparo do DNA , Éxons , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de Sequência de DNA
9.
Bratisl Lek Listy ; 120(5): 349-355, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31113197

RESUMO

X-ray repair cross-complementing group 1 (XRCC1) is a scaffold protein and a key element in DNA base excision repair process. Although, the role of XRCC1 polymorphisms in male infertility has been studied broadly, it is still a matter of debate. Hence, in order to shed light on the problem, we performed a meta-analysis to evaluate the overall effect of XRCC1 polymorphisms in male infertility risk. Databases, Web of Science, PubMed, Scopus, and Google Scholar were searched until September 15, 2018. Afterwards, the genotypes' distribution, genotyping methods, and ethnicity groups were extracted, and overall analyses were conducted. A total number of five researches on 1,407 subjects and 974 controls were found to meet our criteria in this meta-analysis. The XRCC1 Arg399Gln (rs25487) polymorphism was analyzed. This is the first meta-analysis to investigate the association of XRCC1 polymorphisms (codon 399) and male infertility risk. Our results indicated that the XRCC1 Arg399Gln polymorphism was not associated with male infertility risk in the total studied populations (Tab. 2, Fig. 3, Ref. 26). Keywords: meta-analysis; male infertility; polymorphism; XRCC1 Arg399Gln.


Assuntos
Predisposição Genética para Doença , Infertilidade Masculina , Polimorfismo de Nucleotídeo Único , Proteína 1 Complementadora Cruzada de Reparo de Raio-X , Estudos de Casos e Controles , Proteínas de Ligação a DNA , Humanos , Infertilidade Masculina/genética , Masculino , Fatores de Risco , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética
10.
Ecotoxicol Environ Saf ; 179: 135-142, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31035247

RESUMO

Soybean farmers are exposed to various types of pesticides that contain in their formulations a combination of chemicals with genotoxic and mutagenic potential. Therefore, the objective of this paper was to evaluate the genetic damages caused by this pesticide exposure to soybean producers in the state of Mato Grosso (Brazil), regarding biochemical, genetic polymorphic and in silico analyses. A total of 148 individuals were evaluated, 76 of which were occupationally exposed and 72 were not exposed at all. The buccal micronucleus cytome assay (BMCyt) detected in the exposed group an increase on DNA damage and cell death. No inhibition of butyrylcholinesterase (BchE) was observed within the exposed group. The detection of inorganic elements was made through the particle-induced X-ray emission technique (PIXE), which revealed higher concentrations of Bromine (Br), Rubidium (Rb) and Lead (Pb) in rural workers. A molecular model using in silico analysis suggests how metal ions can cause both DNA damage and apoptosis in the exposed cells. Analysis of the compared effect of X-ray Repair Cross-complement Protein 1 (XRCC1) and Paraoxonase 1 (PON1) genotypes in the groups demonstrated an increase of binucleated cells (exposed group) and nuclear bud (non-exposed group) in individuals with the XRCC1 Trip/- and PON1 Arg/- genes. There was no significant difference in the telomere (TL) mean value in the exposed group in contrast to the non-exposed group. Our results showed that soybean producers showed genotoxic effect and cell death, which may have been induced by exposure to complex mixtures of agrochemicals and fertilizers. In addition, XRCC1 Arg/Arg could, in some respects, provide protection to individuals.


Assuntos
Misturas Complexas/toxicidade , Dano ao DNA , Fertilizantes/toxicidade , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Praguicidas/toxicidade , Polimorfismo Genético , Adulto , Apoptose/efeitos dos fármacos , Arildialquilfosfatase/efeitos dos fármacos , Brasil , Simulação por Computador , Células Epiteliais/efeitos dos fármacos , Fazendeiros , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/citologia , Exposição Ocupacional/análise , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética
11.
Br J Biomed Sci ; 76(2): 64-69, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31025604

RESUMO

BACKGROUND: Hepatitis C virus (HCV) related liver cirrhosis occurs in about 20% of chronically infected patients over a duration of 10-20 years, and within 5 years approximately 10-20% of these cirrhotic patients will develop hepatocellular carcinoma (HCC). Previous studies report that the X-ray repair cross-complementing group1 gene (XRCC1) is important in the risk of HCC development; however, results obtained from these studies are conflicting rather than conclusive. We hypothesised an association between single nucleotide polymorphisms (SNPs) in XRCC1 with the HCC risk on a background of chronic hepatitis C. MATERIALS AND METHODS: We recruited 210 subjects, 70 with HCC, 70 with cirrhosis and 70 healthy controls. Two SNPs [c.1254C>T(rs2293035) and c.1517G>C(rs139599857)] in XRCC1 were genotyped using created restriction site-polymerase chain reaction (CRS-PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS: The TT genotype, CT genotype and T-allele in c.1254C>T (rs2293035) were linked to risk of HCC compared to the CC genotype: OR 3.58 [confidence interval (CI) 95%: 1.19-10.7] p = 0.019; OR 2.16 (CI 95%: 1.04-4.47) p = 0.037 and OR 2.10 (CI 95%: 1.2-3.3) p = 0.006, respectively. Regarding c.1517G>C (rs139599857), the CC genotype, GC genotype and C-allele were linked with higher risk of developing HCC compared to GG genotype: OR 4.77 (CI 95%: 1.3-16.9), p = 0.016; OR 3.02 (CI 95%: 1.46-6.2), p = 0.002 and OR 2.4 (CI 95%: 1.4-4.0), p = 0.001, respectively. CONCLUSION: We conclude that the T-allele of c.1254C>T (rs2293035) and the C allele of c.1517G>C (rs139599857) genetic variants may be associated with increased HCC risk among chronic hepatitis C patients.


Assuntos
Carcinoma Hepatocelular/genética , Hepatite C Crônica/genética , Neoplasias Hepáticas/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Alelos , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
12.
Br J Biomed Sci ; 76(3): 117-121, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30870085

RESUMO

Background and objective: Carcinoma of cervix is the second most common cancer among women worldwide. The DNA repair network plays an important role in the maintenance of genetic stability, protection against DNA damage and carcinogenesis. Alterations in repair genes XRCC1, XRCC2 and XRCC3 and been reported in certain cancers. We hypothesised an association between XRCC1+399A/G, XRCC2+31467G/A and XRCC3+18067C/T polymorphisms and the risk of cervical cancer. Subjects and methods: This study included 525 subjects (265 controls and 260 cervical cancer cases). Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: Women with GA and AA genotypes of XRCC1+399A/G showed 2.4-3.8 fold higher risk of cervical cancer (P = 0.001). The +399A* allele was significantly linked with cervical cancer (P = 0.002). However, XRCC2+31479G/A and XRCC3+18067C/T polymorphisms did not show any statistically significant associations. Conclusion: The XRCC1+399A/G SNP is linked with cervical cancer. We suggest that this variant can be utilized as a prognostic marker for determination of cervical cancer susceptibility.


Assuntos
Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Neoplasias do Colo do Útero/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Adulto , Idoso , Alelos , Feminino , Frequência do Gene , Genótipo , Humanos , Pessoa de Meia-Idade
13.
Kaohsiung J Med Sci ; 35(1): 39-48, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30844146

RESUMO

An association between genetic polymorphisms in encoding X-ray repair cross complementing group 1 (XRCC1) and encoding xeroderma pigmentosum group D (XPD) and risks of non-small-cell lung cancer (NSCLC) in East Chinese Han population has been observed. Herein we hypothesized that genetic polymorphisms in these two DNA repair genes are likely to be important in the NSCLC in Chinese nonsmoking female patients. We recruited 327 nonsmoking female patients with NSCLC and 342 individuals with benign lung diseases or healthy controls. Genotype frequencies of XRCC1 T-77C, Arg194Trp, Arg280His and Arg399Gln, Pro206Pro, and XPD Asp312Asn and Lys751Gln were calculated after Polymerase Chain Reaction amplification and sequencing. Generalized multifactor dimensionality reduction (GMDR) was used to detect the interactive effect of XRCC1 and XPD gene polymorphisms. The ratio of cooking oil mist exposure history and soot exposure history, and the gene frequencies of XRCC1 T-77C TC + CC, XRCC1 AG + GG, XRCC1 399Gln/Gln, and XPD 751Gln/Gln were higher in female patients with NSCLC than those with benign lung diseases or healthy controls. The haplotypes of XRCC1 T-Arg-Arg-Gln and XRCC1 C-Arg-Arg-Arg were positively associated with the NSCLC occurrence in nonsmoking female patients. GMDR discovered that there was an interactive model of XRCC1 and XPD genes in multiple gene loci. Logistic regression analysis showed that XRCC1 T-77C, XRCC1 Pro206Pro polymorphism, cooking oil mist and soot exposure history and tumor-node-metastasis (TNM) stage were related to NSCLC occurrence for nonsmoking female patients. Taken together, XRCC1 and XPD polymorphisms, cooking oil mist, and soot exposure history may be interactively correlated with NSCLC incidence for nonsmoking female patients.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Interação Gene-Ambiente , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Xeroderma Pigmentoso/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Haplótipos/genética , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Modelos Genéticos , Fatores de Risco , Fumar , Fuligem
14.
Oncol Res Treat ; 42(5): 263-268, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30861523

RESUMO

BACKGROUND: We aimed to detect single nucleotide polymorphisms (SNPs) and mutations in DNA repair genes and their possible association with myelodysplastic syndrome (MDS). METHODS: Targeted enrichment resequencing of 84 DNA repair genes was initially performed on a screening cohort of MDS patients. Real-time polymerase chain reaction was used for genotyping selected SNPs in the validation cohort of patients. RESULTS: A heterozygous frameshift mutation in the XRCC2 gene was identified. It leads to the formation of a truncated non-functional protein and decreased XRCC2 expression level. Decreased expression levels of all DNA repair genes functionally connected with mutated XRCC2 were also present. Moreover, a synonymous substitution in the PRKDC gene and 2 missense mutations in the SMUG1 and XRCC1 genes were also found. In the screening cohort, 6 candidate SNPs were associated with the tendency to develop MDS: rs4135113 (TDG, p = 0.03), rs12917 (MGMT, p = 0.003), rs2230641 (CCNH, p = 0.01), rs2228529 and rs2228526 (ERCC6, p = 0.04 and p = 0.03), and rs1799977 (MLH1, p = 0.04). In the validation cohort, only a polymorphism in MLH1 was significantly associated with development of MDS in patients with poor cytogenetics (p = 0.0004). CONCLUSION: Our study demonstrates that genetic variants are present in DNA repair genes of MDS patients and may be associated with susceptibility to MDS.


Assuntos
Reparo do DNA , Proteínas de Ligação a DNA/genética , Mutação , Síndromes Mielodisplásicas/genética , Análise Mutacional de DNA , Proteína Quinase Ativada por DNA/genética , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Síndromes Mielodisplásicas/enzimologia , Síndromes Mielodisplásicas/metabolismo , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Uracila-DNA Glicosidase/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética
15.
Artigo em Inglês | MEDLINE | ID: mdl-30744807

RESUMO

High fidelity DNA repair is critical to sustain the genomic integrity and quality of developing germ cells. Deficiencies in DNA repair machinery may result in increased DNA damage in germ cell leading to abnormal spermatogenesis and infertility. X-ray repair cross-complementing group 1 (XRCC1) is a testis enriched protein that plays a crucial role in the DNA base excision repair (BER) pathway. The aim of this study was to analyze the level of XRCC1 transcript and protein in infertile men and its association with DNA damage in sperm. A total of eighty infertile patients with different infertile phenotypes (Azoospermia, n = 30; Severe oligozoospermia, n = 25; Severe oligoasthenozoospermia, n = 25) and age-matched controls (normal spermatogenesis [NS], n = 15 and fertile controls, n = 10) were recruited. γ-H2 AX protein levels were analyzed to estimate the DNA damage in sperm. XRCC1 transcript levels in cases and controls were determined by qRT-PCR. XRCC1 and γ-H2 AX proteins were immunohistochemically analyzed in testicular biopsy sections obtained from NOA patients and OA controls. The determination of XRCC1 and γ-H2 AX protein levels was performed with Western blots. The results revealed reduced expression of XRCC1 mRNA and protein in infertile individuals as compared to controls (p < 0.001). γ-H2 AX levels were significantly increased in infertile cases as compared to controls, indicating increased DNA damage in infertile men. The results indicate decreased expression of the XRCC1 gene in infertile patients which may be one of the factors associated with impaired spermatogenesis and infertility.


Assuntos
Dano ao DNA , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Polimorfismo de Nucleotídeo Único , Espermatozoides/patologia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Adulto , Estudos de Casos e Controles , Reparo do DNA , Humanos , Infertilidade Masculina/metabolismo , Masculino , Prognóstico , Espermatozoides/metabolismo , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética
16.
Artigo em Inglês | MEDLINE | ID: mdl-30744808

RESUMO

OBJECTIVE: The base excision repair (BER) pathway and nucleotide excision repair (NER) pathway play important roles in the repair of benzene-induced genetic damage, and the effects of polymorphisms in these pathways on genetic damage and global DNA methylation are of great interest. METHODS: Ten single nucleotide polymorphisms (SNPs) in the BER (XRCC1: rs25489, rs25487; APE1: rs1130409) and NER pathways (XPA: rs1800975; XPC: rs2228000, rs2228002; XPD: rs13181, rs1799793; XPG: rs17655; ERCC1: rs3212986) were analyzed by a Kompetitive allele-specific PCR (KASP) assay to find associations with cytokinesis-block micronucleus (MN) frequency and global DNA methylation in 294 shoe factory workers and 102 control participants. RESULTS: Workers who possessed the following genotypes were associated with high MN frequency: rs25487 AA (FR (95% CI): 1.50 (1.16,1.9), p = 0.002, reference GG); rs1130409 GG (FR (95% CI): 1.28 (1.05,1.55), p = 0.010, reference TT); rs17655 GC (FR (95% CI): 1.18 (1.02,1.38), p = 0.038, reference GG); and rs3212986 TT (FR (95% CI): 1.55 (1.31,1.83), p < 0.001, reference GG). Workers with four and three mutant alleles showed 3.72-fold (OR (95% CI): 3.72 (1.34, 10.03), p = 0.009) and 2.48-fold (OR (95% CI): 2.48 (1.27, 4.88), p = 0.008) increased risk of genetic damage compared with workers with no or one mutant allele, and a dose-response relationship was found by the trend test (p = 0.006). The rs1130409 variant allele (GG+GT) was associated with low global DNA methylation (ß=-0.20, 95% CI: -0.42, 0.03, p = 0.045). CONCLUSION: In benzene-exposed workers, BER and NER pathway polymorphism haplotypes are associated with different levels of chromosome damage and had little effect on global DNA methylation.


Assuntos
Benzeno/efeitos adversos , Biomarcadores/análise , Dano ao DNA , Metilação de DNA , Reparo do DNA , Exposição Ocupacional/efeitos adversos , Polimorfismo de Nucleotídeo Único , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Adulto , Estudos de Casos e Controles , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Genoma Humano , Haplótipos , Humanos , Masculino , Testes para Micronúcleos , Proteínas Nucleares/genética , Prognóstico , Fatores de Transcrição/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Proteína de Xeroderma Pigmentoso Grupo A/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética
17.
BMC Cancer ; 19(1): 24, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616520

RESUMO

BACKGROUND: Cervical cancer is the 4th highest cause of female reproductive tract malignancies. Multiple loci have been identified as important determinant factors for tumor susceptibility. In this report, we aimed to explore the roles of gene polymorphisms affecting x-ray repair cross complementing 1 (XRCC1), the tumor protein p53 (TP53), and fibroblast growth factor receptor 3 (FGFR3) in the context of susceptibility to cervical cancer. Additionally, we assessed the impact of single nucleotide polymorphism-single nucleotide polymorphism (SNP-SNP) interaction of these three genes in the context of cervical cancer risk in Chinese women. METHODS: A case-control study consisted of 340 women located in Chongqing. Of these women, 121 were diagnosed with cervical cancer, 118 served as healthy controls, and 101 were specifically recruited elderly patients above the age of 80 who showed no history of cervical cancer. Three SNPs (XRCC1 rs25487, TP53 rs1042522, and FGFR3 rs121913483) were examined using mutation analysis of mismatch amplification PCR (MAMA-PCR) on samples obtained from peripheral blood. RESULTS: Our results indicated that females from southwestern China all exhibited a wild-type phenotype at FGFR3 rs121913483. We also observed that the rs25487 mutation was significantly increased within the cervical cancer population. A 2-locus SNP-SNP interaction pattern (rs25487 and rs1042522) was significantly associated with cervical cancer risk (cases vs. negative controls: OR = 4.63, 95% CI = 1.83-11.75; cases vs. elderly group: OR = 17.61, 95% CI = 4.34-71.50). CONCLUSIONS: This is the first study to identify a novel interaction between the XRCC1 and TP53 genes that is highly associated with susceptibility to cervical cancer risk in a female population in southwestern China.


Assuntos
Proteína Supressora de Tumor p53/genética , Neoplasias do Colo do Útero/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteína Supressora de Tumor p53/sangue , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/epidemiologia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/sangue
18.
J Clin Pathol ; 72(1): 75-80, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30467244

RESUMO

AIM: TP53 and DNA repair polymorphisms have been proposed as cancer risk factors. This study evaluated the usability of TP53 Arg72Pro single-nucleotide polymorphism, X RCC1 Arg399Gln and RAD51 G135C as a low-cost lung adenocarcinoma screening tool. PATIENTS AND METHODS: This case-control study included 78 atients with lung adenocarcinoma and 79 healthy matched controls. TP53, XRCC1 and RAD51 genotyping was done by PCR followed by restriction length polymorphism. Descriptive analyses included genotype and allelic frequencies and deviations of the frequencies from those expected under Hardy-Weinberg equilibrium were assessed using the χ2 test. The OR and 95% CIs were calculated as an estimate of relative risk, with significance set at p value <0.05. RESULTS: The TP53 codon 72 Pro allele and the XRCC1 codon 399 Arg allele in a homozygous state were associated with lung adenocarcinoma (p=0.037; OR (95% CI) 2.42 (1.10 to 5.31)), that is, p=0.037; OR (95% CI) 2.16 (1.08 to 4.33), respectively. Also, carriers of the TP53 codon 72 Pro allele and the XRCC1 codon 399 ArgArg genotype older than 50 showed an even higher risk of developing lung adenocarcinoma (p=0.03 in both cases). CONCLUSIONS: The TP53 codon 72 Arg allele and XRCC1 codon 399 Gln allele are likely to have a protective effect against lung adenocarcinoma, especially in individuals older than 50 years of age. XRCC1 and TP53 genotyping might be a useful low-cost tool for evaluating individual lung cancer risk, leading to earlier detection and management of this disease.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Neoplasias Pulmonares/diagnóstico , Polimorfismo de Nucleotídeo Único/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma de Pulmão/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Códon/genética , Reparo do DNA , Feminino , Frequência do Gene , Técnicas de Genotipagem , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Rad51 Recombinase/genética , Fatores de Risco , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Adulto Jovem
19.
EMBO J ; 38(1)2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30523148

RESUMO

During active DNA demethylation, 5-methylcytosine (5mC) is oxidized by TET proteins to 5-formyl-/5-carboxylcytosine (5fC/5caC) for replacement by unmethylated C by TDG-initiated DNA base excision repair (BER). Base excision generates fragile abasic sites (AP-sites) in DNA and has to be coordinated with subsequent repair steps to limit accumulation of genome destabilizing secondary DNA lesions. Here, we show that 5fC/5caC is generated at a high rate in genomes of differentiating mouse embryonic stem cells and that SUMOylation and the BER protein XRCC1 play critical roles in orchestrating TDG-initiated BER of these lesions. SUMOylation of XRCC1 facilitates physical interaction with TDG and promotes the assembly of a TDG-BER core complex. Within this TDG-BERosome, SUMO is transferred from XRCC1 and coupled to the SUMO acceptor lysine in TDG, promoting its dissociation while assuring the engagement of the BER machinery to complete demethylation. Although well-studied, the biological importance of TDG SUMOylation has remained obscure. Here, we demonstrate that SUMOylation of TDG suppresses DNA strand-break accumulation and toxicity to PARP inhibition in differentiating mESCs and is essential for neural lineage commitment.


Assuntos
Diferenciação Celular/genética , Desmetilação do DNA , Reparo do DNA/fisiologia , Células-Tronco Embrionárias/fisiologia , Sumoilação/fisiologia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , 5-Metilcitosina/metabolismo , Animais , Células Cultivadas , Citosina/análogos & derivados , Citosina/metabolismo , Humanos , Camundongos , Complexos Multiproteicos/metabolismo , Multimerização Proteica/fisiologia
20.
FASEB J ; 33(2): 2301-2313, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30260704

RESUMO

DNA lesions induce recruitment and accumulation of various repair factors, resulting in formation of discrete nuclear foci. Using superresolution fluorescence microscopy as well as live cell and quantitative imaging, we demonstrate that X-ray repair cross-complementing protein 1 (XRCC1), a key factor in single-strand break and base excision repair, is recruited into nuclear bodies formed in response to replication-related single-strand breaks. Intriguingly, these bodies are assembled immediately in the vicinity of these breaks and never fully colocalize with replication foci. They are structurally organized, containing canonical promyelocytic leukemia (PML) nuclear body protein SP100 concentrated in a peripheral layer, and XRCC1 in the center. They also contain other factors, including PML, poly(ADP-ribose) polymerase 1 (PARP1), ligase IIIα, and origin recognition complex subunit 5. The breast cancer 1 and -2 C terminus domains of XRCC1 are essential for formation of these repair foci. These results reveal that XRCC1-contaning foci constitute newly recognized PML-like nuclear bodies that accrete and locally deliver essential factors for repair of single-strand DNA breaks in replication regions.-Kordon, M. M., Szczurek, A., Berniak, K., Szelest, O., Solarczyk, K., Tworzydlo, M., Wachsmann-Hogiu, S., Vaahtokari, A., Cremer, C., Pederson, T., Dobrucki, J. W. PML-like subnuclear bodies, containing XRCC1, juxtaposed to DNA replication-based single-strand breaks.


Assuntos
Núcleo Celular/metabolismo , Quebras de DNA de Cadeia Simples , Replicação do DNA , Proteína da Leucemia Promielocítica/metabolismo , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Antígenos Nucleares/metabolismo , Autoantígenos/metabolismo , Células Cultivadas , Reparo do DNA , Células HeLa , Humanos , Complexo de Reconhecimento de Origem/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Domínios Proteicos
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