RESUMO
Helicobacter pylori (H. pylori) infection is present in more than half the world's population and has been associated with several gastric disorders, such as gastritis, peptic ulceration, and gastric adenocarcinoma. The clinical outcome of this infection depends on host and bacterial factors where H. pylori virulence genes seem to play a relevant role. Studies of cagA and vacA genes established that they were determining factors in gastric pathogenesis. However, there are gastric cancer cases that are cagA-negative. Several other virulence genes have been searched for, but these genes remain less well known that cagA and vacA. Thus, this review aimed to establish which genes have been suggested as potentially relevant virulence factors for H. pylori-associated gastrointestinal diseases. We focused on the cag-pathogenicity island, genes with adherence and motility functions, and iceA based on the relevance shown in several studies in the literature.
Assuntos
Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Gastropatias/genética , Gastropatias/microbiologia , Animais , Aderência Bacteriana , Proteínas da Membrana Bacteriana Externa/genética , Gastrite/microbiologia , Ilhas Genômicas , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Humanos , Inflamação/microbiologia , Úlcera Péptica/microbiologia , Estômago/microbiologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Virulência , Fatores de Virulência/genéticaRESUMO
AIM: Interleukin polymorphisms and Helicobacter pylori infection are believed to play critical roles in DNA methylation, a process frequently associated with carcinogenesis. The aim of this study was to determine the associations between interleukin polymorphisms and methylation status of three genes related to gastric cancer. Furthermore, the influence of the H. pylori strains was evaluated. MATERIALS & METHODS: 75 gastric tumor samples had the DNA extracted for interleukin polymorphisms genotyping by PCR-RFLP, promoter methylation by MS-PCR and detection and subtyping of H. pylori by PCR. RESULTS: In the cardia tumors, methylation in the COX-2 promoter was associated with IL1RN*2 (p = 0.015), and the associated genotypes IL1B511T + IL1RN*2 seem to be important in the methylation of COX-2 (p = 0.013), especially in the presence of cagA(+) (p = 0.026) and vacAs1 (p = 0.025) H. pylori strains. The associated genotypes IL6 CC+TNF GG seem to be involved in the unmethylation of CDKN2A (p = 0.046), along with H. pylori cagA(+) infection. CONCLUSION: DNA methylation in gastric cancer seems to be influenced by the presence of interleukin polymorphisms and by the H. pylori cagA/vacAs1m1 strains.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Ciclo-Oxigenase 2/genética , Metilação de DNA/genética , Interleucina-6/genética , Neoplasias Gástricas/genética , Idoso , Proteínas de Bactérias/genética , Epigênese Genética/genética , Feminino , Estudos de Associação Genética , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Helicobacter pylori/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras Genéticas , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologiaRESUMO
Polymorphisms in genes encoding enzymes of folate metabolism are a focus of breast cancer risk studies due of the role of these enzymes in DNA methylation, synthesis, and repair. MTHFR, encoding for 5,10-methylenetetrahydrofolate reductase, is one of the most studied genes in this regard, but findings are controversial, and the majority of studies have analyzed polymorphisms individually. In this case control study, we examined the combination of the polymorphisms MTHFR C677T and A1298C with MTR A2756G, where MTR, methionine synthase, is an important enzyme of the folate cycle in the methylation pathway. One hundred and forty-two patients with breast cancer and controls were included and the genotypes were determined using PCR-RFLP. In the population studied, individuals carrying the polymorphic allele in the heterozygous state for both enzymes, MTHFR C677T and MTR A2756G, had an increased risk [odds ratio, OR=2.77 (95% confidence interval, CI=1.19-6.52)] for disease, compared to those with the wild genotype. In addition, individuals carrying the MTR 2756 genotype AG had an increased risk when this was combined with the MTHFR 1298 genotype CC [OR=5.13 (95% CI=0.87-38.82)]. No significant results were found from the analyses associating the MTHFR C677T and A1298C genotypes. However, when stratifying the patients by age (50 years old as the cut-off), patients over 50 years old had greater risk, with the presence of both MTHFR polymorphisms in the heterozygous state [OR=5.33 (95% CI=1.42-21.03)]. This study points out the importance of the interactions between the MTHFR C677T, MTHFR A1298C and MTR A2756G polymorphisms, and also highlights the relevance of the MTR A2756G polymorphism and age in breast cancer risk.
Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Fatores Etários , Brasil , Feminino , Genótipo , Humanos , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de RiscoRESUMO
Two important polymorphisms of folate cycle enzymes, methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase (TS) enhancer region (TSER) 28-bp tandem repeat, are related to risk of various types of cancer, including brain tumors, although there are few studies on this subject. A case-control study of these two polymorphisms in astrocytomas of different grades was carried out using polymerase chain reaction-restriction fragment length polymorphism, also determining the immunohistochemical expression of TS. The MTHFR 677 TT genotype was less associated with astrocytic tumors (odds ratio [OR]=0.00; p=0.0238), but the TSER polymorphism did not show any significant association. Combined genotype TT-double repeats/triple repeats (2R/3R) had a protective effect against astrocytomas (OR=0.00; p=0.0388). Expression of TS protein was observed in the majority of cases, with grade IV tumors being the exception. Moreover, the median H-score for the pilocytic astrocytomas was significantly higher when compared with that for diffuse tumors. There was an inverse correlation between the 2R/2R genotype and the highest TS-expressing tumors, and 3R/3R was relatively more frequent among the tumors grouped in the third and fourth quartiles. Our results provide support for the role of MTHFR and TS polymorphism in gliomagenesis, possibly because of the alteration of DNA methylation and repair status. Moreover, high levels of TS expression were detected in these tumors.