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1.
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
2.
Gut ; 68(12): 2129-2141, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31366457

RESUMO

OBJECTIVE: Chronic inflammation is a risk factor in colorectal cancer (CRC) and reactive oxygen species (ROS) released by the inflamed stroma elicit DNA damage in epithelial cells. We sought to identify new drivers of ulcerative colitis (UC) and inflammatory CRC. DESIGN: The study uses samples from patients with UC, mouse models of colitis and CRC and mice deficient for the epithelial-to-mesenchymal transition factor ZEB1 and the DNA repair glycosylase N-methyl-purine glycosylase (MPG). Samples were analysed by immunostaining, qRT-PCR, chromatin immunoprecipitation assays, microbiota next-generation sequencing and ROS determination. RESULTS: ZEB1 was induced in the colonic epithelium of UC and of mouse models of colitis. Compared with wild-type counterparts, Zeb1-deficient mice were partially protected from experimental colitis and, in a model of inflammatory CRC, they developed fewer tumours and exhibited lower levels of DNA damage (8-oxo-dG) and higher expression of MPG. Knockdown of ZEB1 in CRC cells inhibited 8-oxo-dG induction by oxidative stress (H2O2) and inflammatory cytokines (interleukin (IL)1ß). ZEB1 bound directly to the MPG promoter whose expression inhibited. This molecular mechanism was validated at the genetic level and the crossing of Zeb1-deficient and Mpg-deficient mice reverted the reduced inflammation and tumourigenesis in the former. ZEB1 expression in CRC cells induced ROS and IL1ß production by macrophages that, in turn, lowered MPG in CRC cells thus amplifying a positive loop between both cells to promote DNA damage and inhibit DNA repair. CONCLUSIONS: ZEB1 promotes colitis and inflammatory CRC through the inhibition of MPG in epithelial cells, thus offering new therapeutic strategies to modulate inflammation and inflammatory cancer.


Assuntos
Colite Ulcerativa/genética , Neoplasias do Colo/genética , DNA Glicosilases/genética , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Experimentais , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Animais , Biópsia , Células Cultivadas , Colite Ulcerativa/complicações , Colite Ulcerativa/metabolismo , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , DNA Glicosilases/metabolismo , Reparo do DNA , Células Epiteliais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Neoplásico/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Dedos de Zinco
3.
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
4.
Environ Sci Pollut Res Int ; 26(26): 26553-26562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31292876

RESUMO

Our study evaluated 163 individuals, being 74 soybean farmers, occupationally exposed to pesticides, and 89 individuals from Goias municipalities, Central Brazil, with similar conditions to the exposed group, comprising the control group. Of the 74 soybean farmers, 43 exposed directly to pesticides and 31 exposed indirectly. The exposed group consisted of individuals aged 19 to 63 years, 21 women and 53 men, and the control group had ages ranging from 18 to 64 years, being 36 women and 53 men. 18.9% of the exposed group were poisoned by pesticides, and the most common symptoms were headache and gastrointestinal problems. The genotype frequencies of the rs2031920 (T>C) polymorphism in the CYP2E1 gene present significant differences between the exposed and control groups (p = 0.02), showing that 24.3% of the exposed group were heterozygotes against 6.7% in the control group. For the OGG1 gene, two SNPs, rs1052133 (G>C) and rs293795 (T>C), were evaluated and the genotype frequencies were not statistically different between the exposed and control groups. The DNA damage was distinct (p < 0.05) in the three analyzed comet parameters (tail length, Olive tail moment, %DNA) between groups. However, there was no influence of age and alcohol consumption between the groups associated with the polymorphisms in the CYP2E1 and OGG1 genes and DNA damage. We also did not find altered hematological and biochemical parameters in the exposed group. Thus, this pioneering study at Goias State carried out an overview of the health of soybean farmers. We evaluated classic laboratory exams, associated with exposure markers (comet assay) and susceptibility markers (genetic polymorphisms), emphasizing the need to expand the Brazilian health assessment protocol. We found, in soybean farmers, increased DNA damage and a higher number of heterozygotes in CYP2E1 gene, compared with the control group, despite the lack of association with age, educational level, smoking, drinking habits, and genetic polymorphisms.


Assuntos
Citocromo P-450 CYP2E1/genética , Dano ao DNA , DNA Glicosilases/genética , Reparo do DNA , Fazendeiros , Polimorfismo Genético , Adolescente , Adulto , Idoso , Poluentes Ocupacionais do Ar/análise , Poluentes Ocupacionais do Ar/toxicidade , Biomarcadores/sangue , Brasil , Ensaio Cometa , Feminino , Humanos , Inativação Metabólica/genética , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/análise , Praguicidas/análise , Praguicidas/toxicidade , Soja/crescimento & desenvolvimento , Adulto Jovem
5.
Ter Arkh ; 91(2): 97-100, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-31094179

RESUMO

MutYH-associated polyposis is the only polyposis syndrome with an autosomal recessive type of inheritance, often phenotypically similar to a weakened form of familial adenomatous polyposis. For the development of the disease mutations in both alleles of the gene are required, but an increased risk of developing colorectal cancer in carriers of monoallelic mutations is noted. The diagnosis of MutYH-associated polyposis should be suspected in a patient with colorectal cancer over 45 years old on the background of polyps in the colon. The review presents modern algorithms for diagnostic and treatment of the disease.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , DNA Glicosilases/genética , Predisposição Genética para Doença/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo
6.
Medicine (Baltimore) ; 98(17): e15359, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027119

RESUMO

This study was performed to investigate the relationship between the MUTYH Gln324His (CAG/CAC) genotype and risk of cervical squamous cell carcinoma (CSCC) in a case-control setting. Mismatch amplification-polymerase chain reaction (MA-PCR) was applied to detect the polymorphism in 400 CSCC, 400 CIN III and 1200 control participants. The homozygous His324His (CAC/CAC) genotype of MUTYH was associated with significantly increased risk of CIN III (OR = 1.94) and CSCC (OR = 3.83). Increased risk of CIN III (OR = 1.34) and CSCC (OR = 1.97) was additionally observed with the heterozygous CAG/CAC genotype. Overall, individuals in both CAC/CAC and CAG/CAC genotype groups were at higher risk of cervical carcinoma (CINIII (OR = 1.46) and CSCC (OR = 2.34)). Within the HR-HPV infection-positive group, CAC/CAC and CAG/CAC genotypes were significantly enriched in relation to CIN III and CSCC. Moreover, we observed a positive correlation between the proportion of homozygous CAC/CAC MUTYH genotype and malignant prognostic factors of CSCC, such as cell differentiation grade and lymph node metastasis. These findings clearly highlight associations between the MUTYH Gln324His (CAG/CAC) polymorphism and susceptibility to CSCC, HR-HPV infection and specific prognostic factors, supporting the utility of this variant as an early indicator for patients at high risk of cervical carcinoma.


Assuntos
Carcinoma de Células Escamosas/genética , DNA Glicosilases/genética , Predisposição Genética para Doença , Infecções por Papillomavirus/genética , Polimorfismo de Nucleotídeo Único , Neoplasias do Colo do Útero/genética , Adulto , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/virologia , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Metástase Linfática/genética , Gradação de Tumores , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/enzimologia , Prognóstico , Neoplasias do Colo do Útero/complicações , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/virologia
7.
BMC Cancer ; 19(1): 324, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953464

RESUMO

BACKGROUND: We are reporting a rare case of MUTYH-associated polyposis, a colorectal cancer hereditary syndrome, diagnosticated after an intussusception. Colorectal cancer is an important cause of cancer related mortality that can be manifested by an intussusception, a rare occurrence in adults and almost always related to tumors. Approximately 5% of colorectal cancers can be attributed to syndromes known to cause hereditary colorectal cancer, such as MUTYH-associated polyposis, autosomal genetic syndrome associated with this disease. CASE PRESENTATION: We present the case of a 44 years old male, that sought medical consultation with a complaint of abdominal discomfort, that after five days changed its characteristics. The patient was sent to the emergency department were a CT-scan revealed intestinal sub-occlusion by ileocolic invagination. Right colectomy was carried out. The anatomic-pathological examination revealed a moderately differentiated mucinous adenocarcinoma and multiples sessile polyps, which led to the suspicion of a genetic syndrome. In the genetics analysis two mutations were observed in the MUTYH gene, and MUTYH-associated polyposis was diagnosticated. CONCLUSION: This case demonstrates the importance of meticulous analysis of the patient examinations results to identify possible discrete alterations that can lead to improved understanding of disease.


Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Polipose Adenomatosa do Colo/diagnóstico , DNA Glicosilases/genética , Doenças do Íleo/etiologia , Intussuscepção/etiologia , Adenocarcinoma Mucinoso/complicações , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/cirurgia , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/cirurgia , Adulto , Colectomia , Colo/diagnóstico por imagem , Colo/patologia , Colo/cirurgia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Doenças do Íleo/diagnóstico por imagem , Doenças do Íleo/cirurgia , Intussuscepção/diagnóstico por imagem , Intussuscepção/cirurgia , Masculino , Tomografia Computadorizada por Raios X
8.
DNA Repair (Amst) ; 76: 76-88, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30822689

RESUMO

During its life cycle, the protist parasite Entamoeba histolytica encounters reactive oxygen and nitrogen species that alter its genome. Base excision repair (BER) is one of the most important pathways for the repair of DNA base lesions. Analysis of the E. histolytica genome revealed the presence of most of the BER components. Surprisingly, this included a gene encoding an apurinic/apyrimidinic (AP) endonuclease that previous studies had assumed was absent. Indeed, our analysis showed that the genome of E. histolytica harbors the necessary genes needed for both short and long-patch BER sub-pathways. These genes include DNA polymerases with predicted 5'-dRP lyase and strand-displacement activities and a sole DNA ligase. A distinct feature of the E. histolytica genome is the lack of several key damage-specific BER glycosylases, such as OGG1/MutM, MDB4, Mag1, MPG, SMUG, and TDG. Our evolutionary analysis indicates that several E. histolytica DNA glycosylases were acquired by lateral gene transfer (LGT). The genes that encode for MutY, AlkD, and UDG (Family VI) are included among these cases. Endonuclease III and UNG (family I) are the only DNA glycosylases with a eukaryotic origin in E. histolytica. A gene encoding a MutT 8-oxodGTPase was also identified that was acquired by LGT. The mixed composition of BER genes as a DNA metabolic pathway shaped by LGT in E. histolytica indicates that LGT plays a major role in the evolution of this eukaryote. Sequence and structural prediction of E. histolytica DNA glycosylases, as well as MutT, suggest that the E. histolytica DNA repair proteins evolved to harbor structural modifications that may confer unique biochemical features needed for the biology of this parasite.


Assuntos
Reparo do DNA/genética , Entamoeba histolytica/genética , Evolução Molecular , Duplicação Gênica , Transferência Genética Horizontal , Genes de Protozoários/genética , Sequência de Aminoácidos , DNA Glicosilases/química , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Entamoeba histolytica/enzimologia , Humanos , Modelos Moleculares , Conformação Proteica
9.
Asian Pac J Cancer Prev ; 20(3): 925-928, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30912416

RESUMO

Background: In some cancer cells, the OGG1 gene is somatically mutated and highly populated. This study was conducted to examine whether OGG1 rs1052133 polymorphism is associated with the genetic background of chronic myelogenous leukaemia (CML) in Sudan. Methods: A total of 332 CML patients and 70 healthy controls were included in this study. Overall, the genotypes (P=0.0000) and allele (C vs. G, P=0.0007) differed considerably in the frequencies of OGG1 rs1052133 polymorphism between CML patients and controls. Our study is the first to evaluate the association of polymorphism with CML risk with OGG1 rs1052133. Results: A statistically significant association was observed between the genotype distribution of OGG1 rs1052133 polymorphism and CML (P=0.0000) patients. A similar result was also observed in the allele distribution (C vs. G, P=0.0007) compared with healthy controls when compared OGG1 rs1052133 genotypes with CML stages. Results: Genotype and allele frequencies of OGG1 rs1052133 among CML patients. A statistically significant association was observed between the genotype distribution of the OGG1 rs1052133 polymorphism and CML patients (P=0.0000). A similar result was also observed in the allele distribution (C vs. G, P=0.0007) compared with healthy controls with stages of CML in OGG1 rs1052133 genotypes. Conclusion: The results suggest that single nucleotide polymorphism in the gene involved in the restoration of DNA base excision (OGG1 rs1052133) can play a key role in the risk of appearance of CML. To clarify the role of OGG1 in the genetic basis of CML, further case control with larger sample sizes and fine-mapping is required.


Assuntos
DNA Glicosilases/genética , Predisposição Genética para Doença , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Feminino , Seguimentos , Genótipo , Humanos , Incidência , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Sudão/epidemiologia
10.
Nucleic Acids Res ; 47(9): 4569-4585, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30838409

RESUMO

UNG is the major uracil-DNA glycosylase in mammalian cells and is involved in both error-free base excision repair of genomic uracil and mutagenic uracil-processing at the antibody genes. However, the regulation of UNG in these different processes is currently not well understood. The UNG gene encodes two isoforms, UNG1 and UNG2, each possessing unique N-termini that mediate translocation to the mitochondria and the nucleus, respectively. A strict subcellular localization of each isoform has been widely accepted despite a lack of models to study them individually. To determine the roles of each isoform, we generated and characterized several UNG isoform-specific mouse and human cell lines. We identified a distinct UNG1 isoform variant that is targeted to the cell nucleus where it supports antibody class switching and repairs genomic uracil. We propose that the nuclear UNG1 variant, which in contrast to UNG2 lacks a PCNA-binding motif, may be specialized to act on ssDNA through its ability to bind RPA. RPA-coated ssDNA regions include both transcribed antibody genes that are targets for deamination by AID and regions in front of the moving replication forks. Our findings provide new insights into the function of UNG isoforms in adaptive immunity and DNA repair.


Assuntos
DNA Glicosilases/genética , Reparo do DNA/genética , Switching de Imunoglobulina/genética , Recombinação Genética/genética , Uracila-DNA Glicosidase/genética , Animais , Sistemas CRISPR-Cas/genética , Linhagem Celular , Núcleo Celular/genética , Replicação do DNA/genética , DNA de Cadeia Simples/genética , Técnicas de Inativação de Genes , Genoma/genética , Humanos , Camundongos , Antígeno Nuclear de Célula em Proliferação/genética , Isoformas de Proteínas/genética , Uracila/metabolismo
11.
Int J Biol Markers ; 34(1): 80-89, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30852976

RESUMO

BACKGROUND: The goal of this study was to screen point mutations and deletions in APC and MUTYH genes in patients suspected of familial adenomatous polyposis (FAP) in a Brazilian cohort. METHODS: We used high-resolution melting, Sanger direct sequencing and multiplex ligation-dependent probe association (MLPA) assays to identify point mutations, and large genomic variations within the coding regions of APC and MUTYH genes. RESULTS: We identified 19 causative mutations in 40 Brazilian patients from 20 different families. Four novel mutations were identified in the APC gene and two in the MUTYH gene. We also found a high intra- and inter-familial diversity regarding extracolonic manifestations, and gastric polyps were the most common manifestation found in our cohort. CONCLUSION: We believe that the FAP mutational spectrum can be population-specific and screening FAP patients in different populations can improve pre-clinical diagnosis and improve clinical conduct.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Biomarcadores Tumorais/genética , DNA Glicosilases/genética , Predisposição Genética para Doença , Mutação , Polipose Adenomatosa do Colo/patologia , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Adulto Jovem
12.
BMC Res Notes ; 12(1): 92, 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30777129

RESUMO

OBJECTIVES: Reactive oxygen species (ROS) oxidize guanine residues in DNA to form 7,8-dihydro-oxo-2'-deoxyguanosine (8oxoG) lesions in the genome. Human 8-oxoguanine glycosylase-1 (hOGG1) recognizes and excises this highly mutagenic species when it is base-paired opposite a cytosine. We sought to characterize biochemically several hOGG1 variants that have been found in cancer tissues and cell lines, reasoning that if these variants have reduced repair capabilities, they could lead to an increased chance of mutagenesis and carcinogenesis. RESULTS: We have over-expressed and purified the R46Q, A85S, R154H, and S232T hOGG1 variants and have investigated their repair efficiency and thermostability. The hOGG1 variants showed only minor perturbations in the kinetics of 8oxoG excision relative to wild-type hOGG1. Thermal denaturation monitored by circular dichroism revealed that R46Q hOGG1 had a significantly lower Tm (36.6 °C) compared to the other hOGG1 variants (40.9 °C to 43.2 °C). Prolonged pre-incubation at 37 °C prior to the glycosylase assay dramatically reduces the excision activity of R46Q hOGG1, has a modest effect on wild-type hOGG1, and a negligible effect on A85S, R154H, and S232T hOGG1. The observed thermolability of hOGG1 variants was mostly alleviated by co-incubation with stoichiometric amounts of competitor DNA.


Assuntos
DNA Glicosilases/metabolismo , Reparo do DNA/fisiologia , Guanina/análogos & derivados , Desnaturação de Ácido Nucleico , DNA Glicosilases/genética , Reparo do DNA/genética , Guanina/metabolismo , Humanos , Mutação
13.
Genet Test Mol Biomarkers ; 23(2): 138-144, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30648893

RESUMO

AIM: This study investigated the association of the human 8-oxoguanine glycosylase 1 (hOGG1) Ser326Cys polymorphism with risk of cervical squamous cell carcinoma (CSCC) and high-risk human papilloma virus (HR-HPV) infection. BACKGROUND: The hOGG1 Ser326Cys polymorphism is reported to be correlated with the risk of several cancers. However, there are reports that have found no significant differences in the frequency of the hOGG1 Ser326Cys between cervical carcinoma patients and controls. METHODS: hOGG1 Ser326Cys was genotyped through modified allele mismatch amplification polymerase chain reaction in 1200 healthy controls, 400 cervical intraepithelial neoplasia (CIN) grade III cases, and 400 CSCC cases. RESULTS: The homozygous genotype of hOGG1 Cys326Cys (GG) was associated with increased risk of CIN III (odds ratio, OR = 1.81 [1.31-2.49], p < 0.001) and CSCC (OR = 3.05 [2.2-4.20], p < 0.001). The G allele or G carrier (GG + CG) genotype was a highly-significant risk factor for CSCC (OR = 1.49 [1.14-1.97], p = 0.004). In the HR-HPV-positive group, the homozygous genotype of hOGG1 GG was associated with increased risk of CSCC (OR = 3.66 [2.02-6.62], p < 0.001) and risk of CIN III (OR = 1.82 [1.08-3.06], p = 0.024). The proportion of G allele carriers was significantly increased in CIN III (51.9%, [322/620], OR = 1.33 [1.03-1.72], p = 0.028) and CSCC (62.1% [221/356], OR = 2.02 [1.51-2.71], p < 0.001). The GG and GC genotypes were consistently identified as significant risk factors for CSCC (OR = 1.73 [1.06-2.83], p = 0.029) in the HR-HPV infected group. We further observed enrichment of the hOGG1 Ser326Cys polymorphism in the CIN III (p = 0.021) and CSCC (p < 0.001) stratified by age at first intercourse, with more significant enrichment (p = 0.036) in the HR-HPV infection group. CONCLUSIONS: Our findings support associations of the hOGG1 Ser326Cys polymorphism with CSCC carcinogenesis and susceptibility to HR-HPV infection. The hOGG1 Ser326Cys polymorphism may serve as a potential genetic biomarker of susceptibility to cervical cancer and HR-HPV infection.


Assuntos
DNA Glicosilases/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma de Células Escamosas/genética , Estudos de Casos e Controles , China/epidemiologia , DNA Glicosilases/metabolismo , Reparo do DNA/genética , Feminino , Frequência do Gene/genética , Marcadores Genéticos , Predisposição Genética para Doença/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Razão de Chances , Papillomaviridae/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
14.
Anaesthesia ; 74(4): 434-440, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30675716

RESUMO

Observational studies have highlighted the detrimental health effects of shift work. The mechanisms through which acute sleep deprivation may lead to chronic disease have not been elucidated, but it is thought that increased DNA damage or decreased repair can lead to disease. The objective of this study was to examine the effects of acute sleep deprivation on DNA damage. This was a cross-sectional observational study on 49 healthy, full-time doctors. Baseline blood was sampled from each participant after three consecutive days of adequate sleep. Participants (n = 24) who were required to work overnight on-site had additional blood sampled on a morning after acute sleep deprivation. DNA damage and expression of DNA repair genes were quantified. Information on health, working patterns and sleep diaries were collected. Independent t-tests were used to compare differences between groups and standardised mean differences expressed as Cohen's d. Overnight on-site call participants had lower baseline DNA repair gene expression and more DNA breaks than participants who did not work overnight (d = 1.47, p = 0.0001; and 1.48, p = 0.0001, respectively). In overnight on-site call participants, after acute sleep deprivation, DNA repair gene expression was decreased (d = 0.90, p = 0.0001) and DNA breaks were increased (d = 0.87, p = 0.0018). Sleep deprivation in shift workers is associated with adverse health consequences. Increased DNA damage has been linked to the development of chronic disease. This study demonstrates that disrupted sleep is associated with DNA damage. Furthermore, larger prospective studies looking at relationships between DNA damage and chronic disease development are warranted, and methods to relieve, or repair, DNA damage linked to sleep deprivation should be investigated.


Assuntos
Dano ao DNA , Médicos , Privação do Sono/genética , Transtornos do Sono do Ritmo Circadiano/complicações , Adulto , Estudos Transversais , DNA Glicosilases/genética , Reparo do DNA , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Feminino , Humanos , Masculino
15.
Dis Colon Rectum ; 62(4): 470-475, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30640315

RESUMO

BACKGROUND: Almost no prospective data on endoscopy in MUTYH monoallelic carriers are available. OBJECTIVE: This study aimed to define the prevalence of colorectal and duodenal adenomas in a population of people presenting with a single mutation of the MUTYH gene and being first-degree relatives of biallelic MUTYH mutation carriers. DESIGN: This study is a prospective cohort evaluation. PATIENTS: Patients were first-degree relatives of a patient who had polyposis with biallelic MUTYH mutation and carrying a single gene mutation of the gene from 12 French centers. SETTINGS: This is a multicenter study. INTERVENTION: Detailed data on life habits (tobacco, alcohol, and nonsteroidal anti-inflammatory drugs), extraintestinal manifestations, and germline analysis were recorded. Complete endoscopic evaluation (colonoscopy and upper endoscopy) with chromoendoscopy was performed. RESULTS: Sixty-two patients were prospectively included (34 women (55%), mean age of 54, range 30-70 years). Thirty-two patients (52%) presented with colorectal polyps at colonoscopy. Of these patients with polyps, 15 (25%) had only adenomas, 8 (13%) had only hyperplastic polyps, 1 (1%) had sessile serrated adenomas, and 8 (13%) had adenomas and/or sessile serrated adenomas. We detected, in total, 29 adenomas with low-grade dysplasia, 5 adenomas with high-grade dysplasia, and 6 sessile serrated adenomas. Fourteen patients (23%) presented with a single adenoma, and 10 (16%) had 1 to 5 adenomas. No patient had more than 5 adenomas. At upper endoscopy, 3 had a limited number of fundic gland polyps; none had duodenal adenomas. The 2 main missense mutations c.1145G>A, p.Gly382Asp and c.494A>G, p.Tyr165Cys were associated with the development of colorectal adenomas/serrated polyps in these monoallelic carriers. LIMITATIONS: This study was limited by the small number of patients. CONCLUSIONS: This prospective study provides unique prospective data suggesting that monoallelic mutation carriers related to patients with polyposis show no colorectal polyposis and have very limited upper GI manifestations justifying an endoscopic follow-up. See Video Abstract at http://links.lww.com/DCR/A862.


Assuntos
Adenoma , Polipose Adenomatosa do Colo , Neoplasias Colorretais , DNA Glicosilases/genética , Neoplasias Duodenais , Endoscopia do Sistema Digestório/métodos , Adenoma/genética , Adenoma/patologia , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Corantes/farmacologia , Neoplasias Duodenais/genética , Neoplasias Duodenais/patologia , Saúde da Família , Feminino , França/epidemiologia , Humanos , Aumento da Imagem/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Avaliação de Resultados (Cuidados de Saúde) , Estudos Prospectivos
16.
Nucleic Acids Res ; 47(6): 2922-2931, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30649547

RESUMO

The vast majority of oxidized bases that form in DNA are subject to base excision repair (BER). The DNA intermediates generated during successive steps in BER may prove mutagenic or lethal, making it critical that they be 'handed' from one BER enzyme to the next in a coordinated fashion. Here, we report that the handoff of BER intermediates that occurs during the repair of naked DNA substrates differs significantly from that in nucleosomes. During BER of oxidized bases in naked DNA, products generated by the DNA glycosylase NTHL1 were efficiently processed by the downstream enzyme, AP-endonuclease (APE1). In nucleosomes, however, NTHL1-generated products accumulated to significant levels and persisted for some time. During BER of naked DNA substrates, APE1 completely bypasses the inefficient lyase activity of NTHL1. In nucleosomes, the NTHL1-associated lyase contributes to BER, even in the presence of APE1. Moreover, in nucleosomes but not in naked DNA, APE1 was able to process NTHL1 lyase-generated substrates just as efficiently as it processed abasic sites. Thus, the lyase activity of hNTHL1, and the 3' diesterase activity of APE1, which had been seen as relatively dispensable, may have been preserved during evolution to enhance BER in chromatin.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA/genética , Desoxirribonuclease (Dímero de Pirimidina)/genética , Nucleossomos/enzimologia , Cromatina/enzimologia , Cromatina/genética , DNA/química , Dano ao DNA/genética , DNA Glicosilases/química , DNA Glicosilases/genética , Reparo do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/química , Desoxirribonuclease (Dímero de Pirimidina)/química , Esterases/genética , Humanos , Liases/química , Liases/genética , Nucleossomos/genética , Oxirredução
17.
Fam Cancer ; 18(2): 203-209, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30604180

RESUMO

Biallelic pathogenic variants (PVs) in MUTYH cause MUTYH-Associated Polyposis (MAP), which displays phenotypic overlap with other hereditary colorectal cancer (CRC) syndromes including Familial Adenomatous Polyposis (FAP) and Lynch syndrome. We report the phenotypic spectrum of MAP in the context of multi-gene hereditary cancer panel testing. Genetic testing results and clinical histories were reviewed for individuals with biallelic MUTYH PVs detected by panel testing at a single commercial molecular diagnostic laboratory. Biallelic MUTYH PVs were identified in 82 individuals (representing 0.2% of tested individuals) with most (75/82; 91.5%) reporting a personal history of CRC and/or polyps. Ten percent (6/61) of individuals reporting polyp number reported fewer than 10 polyps and therefore did not meet current MAP testing criteria. Extracolonic cancers (21/82; 25.6%), multiple primaries (19/82; 23.2%), Lynch-like (17/82; 20.7%) and FAP-like phenotypes (16/82; 19.5%) were observed, including individuals with mismatch repair-deficient tumors (3/82; 3.7%), sebaceous neoplasms (2/82; 2.4%), or congenital hypertrophy of the retinal pigment epithelium (CHRPE) (2/82; 2.4%). We report what is to our knowledge the first cohort of individuals with MAP identified by panel testing. The phenotypic spectrum of MAP observed in this cohort aligns with the published literature. In addition to standard indications for MUTYH testing, our data provide evidence to support consideration of MAP in the differential diagnosis for some individuals with fewer than 10 polyps, depending on other personal and/or family history, as well as for individuals suspected to have Lynch syndrome or FAP.


Assuntos
Polipose Adenomatosa do Colo/genética , Variação Biológica da População/genética , DNA Glicosilases/genética , Neoplasias Primárias Múltiplas/genética , Fenótipo , Polipose Adenomatosa do Colo/diagnóstico , Adulto , Idoso , Alelos , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/diagnóstico , Estudos Retrospectivos
18.
Int J Cancer ; 145(2): 390-400, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30613976

RESUMO

Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non-BRCA1/2 MBC patients were examined in our study. Twenty-seven of the non-BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non-BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.


Assuntos
Neoplasias da Mama Masculina/genética , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Mutação , Análise de Sequência de DNA/métodos , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , DNA Glicosilases/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Nucleic Acids Res ; 47(6): 3058-3071, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30698731

RESUMO

Proper repair of oxidatively damaged DNA bases is essential to maintain genome stability. 8-Oxoguanine (7,8-dihydro-8-oxoguanine, 8-oxoG) is a dangerous DNA lesion because it can mispair with adenine (A) during replication resulting in guanine to thymine transversion mutations. MUTYH DNA glycosylase is responsible for recognizing and removing the adenine from 8-oxoG:adenine (8-oxoG:A) sites. Biallelic mutations in the MUTYH gene predispose individuals to MUTYH-associated polyposis (MAP), and the most commonly observed mutation in some MAP populations is Y165C. Tyr165 is a 'wedge' residue that intercalates into the DNA duplex in the lesion bound state. Here, we utilize single molecule fluorescence microscopy to visualize the real-time search behavior of Escherichia coli and Mus musculus MUTYH WT and wedge variant orthologs on DNA tightropes that contain 8-oxoG:A, 8-oxoG:cytosine, or apurinic product analog sites. We observe that MUTYH WT is able to efficiently find 8-oxoG:A damage and form highly stable bound complexes. In contrast, MUTYH Y150C shows decreased binding lifetimes on undamaged DNA and fails to form a stable lesion recognition complex at damage sites. These findings suggest that MUTYH does not rely upon the wedge residue for damage site recognition, but this residue stabilizes the lesion recognition complex.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Dano ao DNA/genética , DNA Glicosilases/genética , Adenina/metabolismo , Polipose Adenomatosa do Colo/patologia , Animais , Neoplasias Colorretais/patologia , Escherichia coli/genética , Instabilidade Genômica/genética , Guanina/análogos & derivados , Guanina/química , Humanos , Camundongos , Mutação , Estresse Oxidativo/genética
20.
Fam Cancer ; 18(2): 197-201, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30582135

RESUMO

Whether monoallelic MUTYH mutations increase female breast cancer risk remains controversial. This study aimed to determine if monoallelic MUTYH mutations are associated with increased breast cancer risk in women undergoing multigene panel testing (MGPT). The prevalence of monoallelic MUTYH mutations was compared between Non-Hispanic white female breast cancer cases (n = 30,456) and cancer-free controls (n = 12,289), all of whom underwent MGPT that included MUTYH. We tested breast cancer associations with MUTYH alleles using Fisher's exact test, followed by multivariate logistic regression adjusted for age at testing and MGPT type ordered. Frequencies of the two most common MUTYH founder mutations, p.G396D and p.Y179C, were compared independently between the breast cancer cases and MGPT controls, as well as the healthy UK10K control population (n = 2640). Comparing cases to MGPT controls, no association was observed between female breast cancer and any monoallelic MUTYH carrier status (OR 0.86-1.36, p = 0.21-0.96). Similarly, comparisons to UK10K controls revealed no significant increase in breast cancer risk associated with p.G396D (OR 1.20, p = 0.44) or p.Y179C (OR 1.71, p = 0.24). This study did not find a significant increase in breast cancer risk associated with monoallelic MUTYH mutations.


Assuntos
Neoplasias da Mama/genética , DNA Glicosilases/genética , Triagem de Portadores Genéticos/estatística & dados numéricos , Predisposição Genética para Doença , Adulto , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Medição de Risco/métodos
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