京都大学 / 新制・論文博士 / 博士(医学) / 乙第13573号 / 論医博第2299号 / 新制||医||1069(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 藤田 恭之, 教授 伊藤 貴浩 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Les microARNs, régulateurs post-transcriptionnels de l’expression des gènes eucaryotes, sont impliqués dans la défense contre les pathogènes. Afin de favoriser leur multiplication, les virus et les bactéries ont développé des stratégies pour altérer la voie des miRNAs. Dans ce travail, nous avons montré que Helicobacter pylori, une bactérie responsable chez l’Homme de pathologies gastriques sévères, telles que l’ulcère ou le cancer, réprime un cluster de microARNs spécifique des cellules souches embryonnaires dans une lignée épithéliale gastrique. En utilisant une technique de séquençage à haut débit, nous avons identifié miR-372 comme le miRNA le plus exprimé dans cette lignée gastrique. Avec miR-373, miR-372 permet la prolifération cellulaire réprimant l’expression d’un inhibiteur du cycle cellulaire, the LArge Tumor Suppressor 2 (LATS2). Au cours de l’infection par H. pylori, l’expression de miR-372&373 est réprimée, provoquant une accumulation de LATS2 et un arrêt du cycle cellulaire. De manière importante, la répression de ces miRNAs est dépendante de la translocation de l’effecteur bactérien CagA dans la cellule hôte. Ces données constituent un nouvel exemple d’interaction hôte-pathogène impliquant les miRNAs et ont identifié le couple LATS2/miR-372&373 comme un mécanisme inattendu dans l’arrêt du cycle cellulaire observé au cours de l’infection. Ce mécanisme pourrait refléter l’inhibition de l’auto-renouvellement de l’épithélium gastrique, processus impliqué dans la défense contre les infections bactériennes. / MicroRNAs, post-transcriptionnal regulators of eukaryotic gene expression, are implicated in host defense against pathogens. Viruses and bacteria have evolved strategies to suppress miRNA functions with the aim to establish a sustainable infection. In this work, we report that Helicobacter pylori, a bacterium responsible for severe human gastric inflammatory diseases and cancers, down-regulates an embryonic-specific microRNAs cluster in a gastric epithelial cell line. We reveal by using a deep sequencing approach that hsa-miR-372 is the most abundant miRNA expressed in this gastric cell line where, together with hsa-miR-373, it promotes cell proliferation by silencing the expression of a cell cycle inhibitor, the LArge Tumor Suppressor 2 (LATS2). Upon H. pylori infection, miR-372&373 synthesis is inhibited, leading to the derepression of LATS2 and thus, to a cell cycle arrest at the G1/S transition. Importantly, this down-regulation of a specific cell cycle-regulating microRNA is dependent on the translocation of the bacterial effector CagA into the host cells. These data constitute a novel example of host-pathogen interplay involving microRNAs and unveil the couple LATS2/miR-372&373 as an unexpected mechanism in infection-induced cell cycle arrest in proliferating gastric cells which may be relevant of inhibition of gastric epithelium renewal, a major host defense mechanism against bacterial infections.

En raison de l’efficience des traitements, le taux de survie globale à 5 ans des patients avec un cancer gastrique (CG) est d’environ 15%. A l’heure actuelle, il n’existe pas de stratifications des patients permettant de prescrire un protocole de traitements efficace. Durant ma thèse, j’ai établi le rôle de HDAC4 dans la sensibilité des cellules de CG au Cisplatine. J’ai montré que cette réponse semble dépendre du type de CG (intestinal ou diffus) et du statut p53 des cellules cancéreuses. J’ai souligné l’intérêt de combiner un inhibiteur des HDACs (SAHA) avec les chimiothérapies à base de dérivés de platine (PDC : Cisplatine, Oxaliplatine) afin de promouvoir leurs effets cytotoxiques. De manière intéressante, j’ai observé que la réponse aux traitements combinés est différente suivant le statut p53 des cellules cancéreuses. Ces résultats permettent d’ouvrir de nouvelles perspectives dans l’utilisation des traitements combinés PDC + SAHA dans la thérapie du CG. En particulier, le facteur p53 qui est souvent muté dans les CG, pourrait être un marqueur thérapeutique pour un tel protocole de traitement. / Due to the efficiency of treatments, the 5-year overall survival rate for patients with gastric cancer (GC) is approximately 15%. Currently, there is no stratification of patients to prescribe an effective treatment protocol.During my thesis, I established the role of HDAC4 in the sensitivity of GC cells to Cisplatin. I have shown that this response seems to depend on the type of GC (intestinal or diffuse) and the p53 status of cancer cells. I emphasized the interest of combining an HDAC inhibitor (SAHA) with platinum derivative chemotherapies (PDC: Cisplatin, Oxaliplatin) to promote their cytotoxic effects. Interestingly, I observed that the response to combination treatments is different depending on the p53 status of the cancer cells.These results open new perspectives in the use of PDC + SAHA combination therapies in GC. The p53 factor that is often mutated in GC could be a therapeutic marker for a such treatment protocol.

O câncer gástrico já foi descrito associado com Helicobacter pylori e Mycoplasma hyorhnis. Em vista disso, este trabalho avaliou a presença de Mollicutes, M. hyorhinis e H. pylori e suas correlações com câncer gástrico. Foram obtidas 120 amostras de biopsias gástricas embebidas em parafina em Vitória da Conquista - BA, armazenadas no período de 2006-2016. Destes 80 eram de pacientes com câncer gástrico. Para a extração de DNA foi utilizado um kit comercial com desparafinização prévia. A PCR convencional foi aplicada para detecção de Mollicutes, H. pylori e M. hyorhinis, que também foi detectado por qPCR e imuno-histoquímica. Os dados obtidos foram avaliados pelos testes estatísticos de Pearson (X2) e de Mann-Whitney (p 0,05). O grupo controle apresentou maior frequência de Mollicutes (12,3%) e M. hyorhinis (11,0%). H. pylori foi detectado no grupo caso (8,2%) e mas teve maior frequência no grupo controle (22,5%). Não houve coinfecção de Mollicutes, M. hyorhinis e H. pylori no grupo caso, mas o grupo controle apresentou maior prevalência de H. pylori, com associação estatisticamente significativa (p < 0,001). Estes resultados podem direcionar para um aprimoramento de controle e conhecimento de micoplasmas e sua relevância em fenótipos malignos. / Gastric cancer has already been described associated with Helicobacter pylori and Mycoplasma hyorhnis. In view of this, this study evaluated the presence of Mollicutes, M. hyorhinis e H. pylori and its correlations with gastric cancer. 120 samples of gastric biopsies embedded in paraffin were obtained in Vitória da Conquista - BA, stored in the 2006-2016. Of these, 80 were patients with gastric cancer. For DNA extraction a commercial kit with prior dewaxing was used. Conventional PCR was applied for detection of Mollicutes, H. pylori and M. hyorhinis, it which was also detected by qPCR and immunohistochemistry. The data were evaluated by the Pearson (X2) and Mann-Whitney statistical tests (p 0,05). The control group had a higher frequency of Mollicutes (12,3%) and M. hyorhinis (11,0%). H. pylori was detected in the case group (8,2%), but had a higher frequency in the control group (22,5%). There was no coinfection of Mollicutes, M. hyorhinis and H. pylori in the case group, but the control group had a higher prevalence of H. pylori, with a statistically significant association (p < 0,001). These results may lead to improved control and knowledge of mycoplasmas and their relevance to malignant phenotypes.

O rearranjo da anatomia gastrointestinal é atualmente o foco de estudos para a remissão e cura do diabetes mellitus tipo 2. Há evidências a favor da melhora desta comorbidade após a gastrectomia em pacientes não obesos, entretanto sem análise de longo prazo. O intestino grosso, como integrante do aparelho digestório e potencialmente produtor de incretinas, ainda não foi estudado em relação à influência de sua retirada (colectomia) no desfecho do diabetes. Nestas circunstâncias, faz-se necessário um estudo em longo prazo destas duas cirurgias na homeostase glicídica. Objetivos: Analisar a resposta em longo prazo do diabetes e pré-diabetes pré-existentes após gastrectomia, bem como, colectomia por câncer. Métodos: Foram analisados pacientes adultos submetidos à gastrectomia subtotal e total (Y de Roux) por câncer gástrico e colectomia (direita ou retossigmoidectomia) por câncer de colo e reto há mais de 3 anos e sem sinais de doença em atividade. Incluíram-se controles nas duas situações de pós-operatório tardio com homeostase glicídica normal, a fim de averiguar também sua evolução em longo prazo. Agregou-se ainda um grupo controle pré-operatório atual constituído de doentes diabéticos com câncer gástrico, candidatos à gastrectomia curativa, pois alguns exames analisados no pós-operatório não haviam sido coletados no período pré-operatório. Os pacientes foram divididos de acordo com a presença e curso clínico do diabetes. O grupo diabético foi subdividido em Refratários (permaneceram diabéticos) e Responsivos (remissão parcial ou completa). O grupo controle foi dividido em Estáveis (permaneceram sem diabetes) e Neodiabetes (ficaram diabéticos ou pré-diabéticos). Também foram avaliados de acordo com o tipo de cirurgia. Foram coletados exames de albumina, transferrina, ferritina, ferro sérico, hemoglobina, leucócitos, colesterol total, LDL, VLDL e HDL, triglicérides, insulina, hemoglobina A1C, Peptídeo C, IGF-1, Leptina, proteína C reativa, fibrinogênio, tempo de protrombina, dímero D, complemento C3 e C4, ácido fólico e vitamina B12. Peso, altura e perímetro abdominal e do quadril também foram analisados. Resultados: Os seguimentos atingiram 86,8 ± 25,1 meses nos gastrectomizados e 79,2 ±27,4 nos colectomizados. Os pacientes gastrectomizados beneficiaram-se com remissão do diabetes em 41,2% dos casos e os colectomizados em 32,4%. No grupo controle de gastrectomizados surgiram em longo prazo 63,2% de neodiabéticos e no de colectomizados 30,8%. Nos pacientes diabéticos responsivos com câncer gástrico houve paralelismo entre queda da glicemia e do IMC, algo que não se sucedeu nos acometidos de câncer colorretal. Em nenhuma das duas populações refratárias pode-se atribuir um papel para a variação do IMC no desfecho do diabetes. Nos pacientes neodiabéticos nenhuma contribuição do IMC foi despistada em quaisquer dos grupos estudados. Os pacientes diabéticos gastrectomizados e colectomizados não revelaram diferenças significativas nos valores de glicemia e prevalência de diabetes quando separados por tipo de cirurgia. Conclusão: Nos pacientes gastrectomizados, comprovou-se remissão do diabetes a longo prazo ainda que em proporções menores que as documentadas usualmente, com obesos tratados por cirurgia bariátrica. A perda de peso demonstrou influência positiva na resposta do diabetes. A exclusão duodenal pode ser outro fator envolvido na melhora do diabetes ao lado deste moderado emagrecimento. Já a remoção do fundo gástrico não demonstrou influência na evolução destes pacientes. Não há indícios de que a gastrectomia protegeu contra o aparecimento de novos casos de diabetes e pré-diabetes, pois estes se manifestaram em elevadas proporções. Os pacientes colectomizados diabéticos apresentaram taxa ligeiramente menor de responsivos quando comparados com o grupo bariátrico, sem diferenças significativas. A variação do peso e o local de ressecção não se relacionaram com o desfecho do diabetes. As conversões de pacientes normoglicêmicos para diabetes, ao final do tempo de seguimento, foram mais baixas que nos gastrectomizados. São necessários mais estudos para elucidar os mecanismos envolvidos na história natural da homeostase glicídica, tanto após gastrectomia quanto cirurgia colorretal / The rearrangement of gastrointestinal anatomy is currently the focus of research for the cure and remission of type 2 diabetes mellitus. There is evidence suggesting that this comorbidity improves after cancer gastrectomy in non-obese patients, however no long-term analysis is available. The large intestine, as part of the digestive system and potentially producing incretins, has not been studied with regard to the influence of surgical removal (colectomy) on the outcome of diabetes. In these circumstances, a study focusing the long-term outcome of glucose homeostasis after these two surgeries was deemed appropriate. Objectives: Analysis of the long-term response of preexisting diabetes and pre-diabetes after gastrectomy and colectomy for cancer. Population: Adult patients who underwent subtotal and total (Roux-en Y) gastrectomy for gastric cancer, as well as colorectal operation (right hemicolectomy or anterior resection) for colon and rectum cancer, with at least 3 years of follow up and no signs of active disease. Controls with normal glucose homeostasis were included in both contexts, in order to investigate long term evolution also in euglycemic subjects. A current preoperative control group was added consisting of diabetic patients with gastric cancer, aiming to provide information not available in the retrospective analysis of the preoperative period. Patients were divided according to the presence and clinical course of diabetes. The diabetes group was divided into Refractory (remained diabetic) and Responsive cases (partial or complete remission). The control group was similarly divided into Stable (remained without diabetes) and New onset diabetes/NOD (became diabetic or pre-diabetic). Surgical modality was also considered in the stratification (subtotal versus total gastrectomy and right colectomy versus anterior resection). Biochemical tests included albumin, transferrin, ferritin, serum iron, hemoglobin, white blood cell count, total cholesterol, LDL, VLDL, and HDL, triglycerides, insulin, hemoglobin A1C, C-peptide, IGF-1, leptin, C-reactive protein, fibrinogen, prothrombin time, D-dimer, complement C3 and C4, folic acid and vitamin B12. Weight, height and waist/hip ratio were also documented. Results: The follow-up reached 86.8 ± 25.1 months in patients submitted to gastrectomy and 79.2 ± 27.4 in colorectal surgery. Gastrectomized patients benefited from diabetes remission in 41.2% of cases and 32.4% after large bowel operation. NOD was detected in 63.2% and 30.8% of nondiabetic subjects, respectively. Among responsive diabetic patients with gastric cancer direct relation between fall in blood glucose and BMI was demonstrated, but not with colorectal cancer. In both refractory populations BMI failed to correlated with outcome of diabetes. In NOD patients no contribution of BMI was shown in any group either. Prevalence of diabetes was not different when stratified according to type of surgery. Conclusion: In gastrectomized patients, long term remission of diabetes was confirmed, even though is smaller proportions than those reported after bariatric surgery. Weight loss showed a positive influence in the responsive diabetes population submitted to gastrectomy. There are reasons to believe that duodenal exclusion was involved as well in diabetes amelioration, besides moderate weight loss. The removal of the gastric fundus was not relevant for the evolution of these patients. No evidence in favor of gastrectomy protection against the onset of new diabetes and pre-diabetes was detected. On the contrary, these were registered in high proportions. Colorectal diabetic patients had slightly lower rate of response when compared to the gastrectomy group, without significance. Weight shift and location of the resection were unrelated to the outcome of diabetes. NOD cases at the end of follow-up period were less frequent than after gastric surgery. Further studies are needed to elucidate the mechanisms involved in the natural history of glucose homeostasis, after both gastric and colorectal surgery

Introdução: A desnutrição é muito prevalente em pacientes com câncer gástrico e aumenta o risco de morbidade e mortalidade. O objetivo deste estudo foi determinar qual o método de avaliação nutricional melhor prediz a mortalidade de 90 dias. Métodos: Quarenta e quatro pacientes, 29 homens e 15 mulheres; média(DP) 63 anos de idade (10,2) anos (intervalo = 34 a 83), submetidos a ressecções cirúrgicas, nove gastrectomias parciais e 34 (77,3%) gastrectomias totais para os tumores do estômago (Estágio II a IIIa ) foram avaliados no pré-operatório pela Avaliação Subjetiva Global Produzida Pelo Paciente (ASG-PPP), antropometria e métodos laboratoriais como previamente validados em outros estudos. Resultados: Vinte e nove (66%) eram desnutridos pelo método subjetivo, sendo 15 grau A, 18 grau B e 11 casos grau C. A média(DP) de espessura do músculo adutor do polegar da mão dominante (MAPD) foi de 13,2(3,8) mm e a média de albumina sérica(DP) foi de 3,9(0,5)g/dL. Os casos com ASG-PPP-B (p<0,013) e com MAPD ≤10,8mm (p=0,003) foram significativamente associados à maior mortalidade. As curvas ROC (intervalo de confiança de 95%) de ambas ASG-PPP e espessura da MAPD (0,74 e 0,78) fidedignamente predisseram mortalidade em 30 dias e 0,739 e 0,866 respectivamente em 90 dias. Conclusão: ASG-PPP e espessura da MAPD podem ser utilizados como parâmetros pré-operatórios para risco de morte. / Background: Malnutrition is very prevalent in patients with gastric cancer and increases the risk of morbidity and mortality. The aim of this study was to determine which nutritional assessment method better predicts 90-days mortality. Methods: Forty-four patients, 29 men and 15 women; mean(SD) age of 63(10.2) yr (range = 34 to 83), undergoing surgical resections, nine (20,5%) partial gastrectomies and 34(77,3%) total gastrectomies for stomach tumors (Stage II to IIIa) were preoperatively assessed by Patient Generated Subjective Global Assessment (PG-SGA), anthropometry and by laboratory sampling as previously validated in other studies. Results: Twenty-nine (66%) of them were unnourished by the subjective method as 15 grade A, 18 grade B, and 11 grade C cases. Mean(SD) of dominant hand adductor pollicis muscle thickness (DAPMT) was 13.2(3.8) mm and mean(SD) serum albumin was 3.9(0.5)g/dL. PG-SGA grade B cases (P<0.013) and DAPMT ≤10,8mm (P=0,003) were significantly associated with higher mortality. Receiver operating characteristic curves (95% confidence interval) both PG-SGA and DAPMT (0.74 and 0.78) reliably predicted in 30-day and 0.739 and 0.866 respectively in 90-day mortality. Conclusion: PG-SGA and DAPMT may be used as preoperative parameter of risk of death.

Emerging evidence suggests the immune system has a role in preventing cancer, and in advanced cancer evidence of immune dysfunction is widespread. This project focused on cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of T cell activation found on dedicated regulatory T cells (Treg) and activated T lymphocytes, and asked whether modulation of immune control with anti-CTLA4 blockade led to significant anti-tumour activity. Clinical and laboratory investigation of anti-CTLA4 blockade using tremelimumab in a phase II trial of second-line therapy in advanced oesophageal and gastric adenocarcinomas was combined with an attempt to establish a suitable pre-clinical model based on therapeutic vaccination against the tumour associated antigen (TAA) 5T4.Eighteen patients received tremelimumab. Most drug-related toxicity was mild but there was a single death due to bowel perforation. Four patients had stable disease with clinical benefit; one achieved a partial response after eight cycles (25.4 months) and remains well on study after four years. Markers of regulatory phenotype, forkhead box protein 3 (FoxP3) and CTLA4, doubled transiently in CD4+CD25high lymphocytes in the first month after tremelimumab before returning to baseline. In contrast, CTLA4 increased in CD4+CD25low/negative lymphocytes throughout the cycle of treatment. Post-treatment expanded Treg expressed FoxP3 without interleukin-2 and their defining suppressive function was not abolished despite prolonged anti-CTLA4 blockade. De novo proliferative responses to TAA 5T4 (8 of 18 patients) and carcinoembryonic antigen (CEA; 5 of 15) were detected. Patients with a post-treatment CEA proliferative response had median survival of 17.1 months compared to 4.6 months for non-responders (p=0.002). Baseline interleukin-2 release after T lymphocyte activation was higher in patients with clinical benefit and toxicity. Heterologous mouse 5T4 (m5T4) vaccination showed some evidence of weak therapeutic benefit, but all tumour models investigated had rapidly lethal kinetics. Specific m5T4 immune responses could be detected by serum antibody ELISA and IFN-gamma ELISPOT assays in naive animals but were lower frequency than published responses to h5T4, and were further attenuated in tumour-bearing animals. The addition of anti-CTLA4 blockade did not result in significant augmentation of m5T4 specific immunity after vaccination in non tumour-bearing animals and combination treatment was ineffective as therapy in this autologous model. Results are discussed in the context of emerging immunotherapeutics in melanoma and prostate cancer. In the absence of supportive data from the model system it would not be appropriate to pursue combination heterologous 5T4 vaccine with anti-CTLA4 blockade, but in view of the unusual durability of the best response to tremelimumab, and in vitro evidence of enhanced proliferative responses to relevant TAA, further investigation of drug activity may be warranted in metastatic gastric and oesophageal second-line treatment.

Made available in DSpace on 2014-06-11T19:30:55Z (GMT). No. of bitstreams: 0 Previous issue date: 2007Bitstream added on 2014-06-13T20:01:07Z : No. of bitstreams: 1 ferrasi_ac_dr_rcla.pdf: 1030993 bytes, checksum: 9a0fbcc4634e2697322fd343cddaa074 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Gastric cancer (GC) is one of the most common cancer types and it is associated with high mortality frequencies. Although a decrease in the worldwide incidence is observed, the prognosis of this disease still remains poor, mainly when the diagnosis is carried out at advanced stages. Recent evidences have identified DNA methylation as an important mechanism for tumor suppressor gene inactivation. Helicobacter pylori infection is considered one of the most important etiological factors and the CagA gene is associated with more severe pathologies including cancer. Likewise, EBV is another infectious agent that has been associated with gastric carcinoma in at least 10% of the cases. In this study, we determined the promoter methylation status of the CDH1, DAPK, COX2, hMLH1 and CDKN2A and MSI frequency in 89 primary gastric carcinomas and correlated the findings with the presence of H. pylori and EBV infections and also with clinicopathological features of gastric carcinomas. COX2 was the most frequently hypermethylated gene (63.5%) in these patients, followed by DAPK (55.7%), CDH1 (51%), CDKN2A (36%) and hMLH1 (30.3%). In this study, MSI was correlated with hMLH1 methylation, as shown before, and there was an inverse correlation between DAPK hypermethylation and MSI. Also, MSI was inversely correlated with H. pylori CagA+, providing new evidence for the association of MSI and better prognosis.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O cÃncer gÃstrico apresenta, mundialmente, uma elevada taxa de mortalidade, com alta incidÃncia no Brasil, sendo a infecÃÃo com Helicobacter pylori um fator de risco bem estabelecido. Dependendo da presenÃa de genes de virulÃncia como cagA, cagE, vacA e virB11, H. pylori pode causar respostas inflamatÃrias diferenciadas, apresentando grande quantidade de Ãxido nÃtrico (ON) gerado principalmente por iNOS. Quantidade elevada de ON resulta em acÃmulo de espÃcies reativas do oxigÃnio cuja instabilidade causa danos oxidativos no DNA. A integridade genÃmica à garantida por enzimas de reparo importantes como: APE-1, OGG-1, e PARP-1. Polimorfismos genÃticos que modifiquem a atividade dessas enzimas podem influenciar a capacidade de reparo e, portanto, a susceptibilidade do hospedeiro ao desenvolvimento do cÃncer gÃstrico associado à H. pylori. Assim o objetivo deste estudo foi avaliar a associaÃÃo dos polimorfismos C150T em iNOS, T2197G em APE-1, C1245G em OGG-1 e A40676G em PARP-1 com o genÃtipo de H. pylori em 109 amostra de pacientes diagnosticados com adenocarcinomas gÃstricos atendidos em hospitais de Fortaleza, CearÃ. A identificaÃÃo dos polimorfismos foi feita por PCR-RFLP e a detecÃÃo e genotipagem de H. pylori foram feitas por PCR. Os polimorfismos estudados apresentaram as seguintes freqÃÃncias: iNOS - 78% CC, 21,1% CT e 0,9% TT; PARP-1- 69,7% AA, 26,6% AG e 3,7% GG, para OGG-1 56% CC, 39,4% CG, e 4,6% GG e para APE-1 38,5%TT, 47,7%TG e 13,8% GG. Salienta-se a baixa freqÃÃncia do genÃtipo polimÃrfico (TT) de iNOS e alta frequÃncia do heterozigoto (TG) de APE. Os alelos variantes de iNOS e de PARP-1 foram correlacionadas com indivÃduos &#8804;55 anos, sugerindo que estes polimorfismos estariam associados ao desenvolvimento precoce da neoplasia. Os tumores intestinais localizados na regiÃo nÃo-antro correlacionaram-se com o genÃtipo OGG-1 CG; enquanto que os difusos, localizados no corpo com o genÃtipo AA de PARP-1. H. pylori foi detectada em 92,6% dos casos. Os genes cagA, cagE e virB11 foram detectados em 65,3%, 50,4% e 60,3% dos casos, respectivamente e vacAs1m1 detectado em 72,2%. Os casos foram agrupados considerando os alelos de vacA e a integridade da ilha de patogenicidade cag, sendo os grupos A1 e A2, composto por cepas mais patogÃnicas, o qual foi observado em 33,6% e 13,8% dos pacientes, respectivamente. Na anÃlise individual de cada enzima, observou-se que os indivÃduos portadores dos alelos variantes de APE-1 (TG+GG) estavam infectados com cepas pouco patogÃnicas (p=0,0422). Essas cepas pouco patogÃnicas tambÃm foram associadas aos pacientes portadores do genÃtipo selvagem (AA) de PARP-1 (p=0,0396). Esses dados foram confirmados quando os pacientes infectados por cepas mais virulentas foram comparadas aos infectados por cepas menos virulentas (p=0,046). Analisando apenas o grupo A1 observou-se tambÃm uma correlaÃÃo de APE-1 (TG) com OGG-1(CC). Quando os genÃtipos foram combinados considerando somente as enzimas de reparo estudadas ou duas a duas, verificou-se que parte dos pacientes infectados com o genÃtipo selvagem de PARP-1 eram portadores do alelo variante para pelo menos uma das enzimas e que parte dos pacientes infectados com cepas menos patogÃnicas possuÃam o alelo polimÃrfico de APE-1, independente do genÃtipo da enzima de reparo associada. Somados, esses dados indicam a relevÃncia do polimorfismo da APE-1 no desenvolvimento do cÃncer gÃstrico em indivÃduos infectados com cepas menos virulentas e corroboram com a importÃncia do genÃtipo bacteriano, uma vez que, de maneira geral, indivÃduos com genÃtipo selvagem para as enzimas de reparo estudadas desenvolveram cÃncer gÃstrico quando infectados por cepas virulentas. / Gastric cancer is the most deadly malignant neoplasia worldwide, with high incidence in Brazil and Helicobacter pylori infection is a well-established risk factor. Depending on the presence of virulence genes such as cagA, cagE, vacA and virB11, H. pylori can cause differentiated inflammatory responses, with large amounts of nitric oxide (NO) generated primarily by iNOS. High amount of NO resulting in accumulation of reactive oxygen species can cause DNA oxidative damage. The genomic integrity is guaranteed by important repair enzymes as: APE-1, OGG-1 and PARP-1. Genetic polymorphisms that modify the activity of these enzymes may influence the ability to repair and therefore the host susceptibility to the development of gastric cancer H.pylori associated. Therefore, the goal of this study was to evaluate the association of the C150T polymorphism in iNOS, T2197G in APE-1, C1245G in OGG -1 and A40676G in PARP-1 with H.pylori genotype in 109 cases of patients with gastric adenocarcinoma from hospitals in Fortaleza, CearÃ. The identification of polymorphisms was performed by PCR-RFLP and the detection and genotyping of H.pylori were performed by PCR. The studied polymorphisms showed the following frequencies: iNOS 78% CC, 21.1% CT and 0.9% TT; PARP-1 69.7% AA 26.6% AG and 3.7% GG to OGG -1 56% CC, 39.4% CG and 4.6% GG and APE-1 38.5% TT, 47.7% TG and 13.8% GG. Valuable to note the low frequency of the homozygous polymorphic (TT) of iNOS and the high frequency of heterozygous (TG) from APE-1. The variant alleles of iNOS and PARP-1 were correlated with subjects &#8804; 55 years, suggesting that these polymorphisms were associated with early development of the neoplasia. Intestinal tumors located in the non-antrum were correlated with heterozygous genotype of OGG-1 (CG), while diffuse, located on the body with the AA genotype of PARP-1. H. pylori was detected in 92.6% of cases. The genes cagA, cagE and virB11 were detected in 65.3%, 50.4% and 60.3% of cases respectively and vacAs1m1 was detected in 72.2%. The cases were also grouped considering the alleles of vacA and the integrity of the cag-pathogenicity island. Thus, the groups A1 and A2, consist of more pathogenic strains, were observed in 33.6% and 13.8% of patients, respectively. In the individual analysis of each enzyme, we observed that individuals carrying the variant alleles of APE-1 (TG+GG) were infected with low pathogenic strains (p=0.0422). These low pathogenic strains were also associated with patients carrying the wild genotype (AA) of PARP-1 (p=0.0396). These data were confirmed when patients infected with more virulent strains were compared to those infected with less virulent strains (p = 0.046). Analyzing only the group A1, it was also observed a correlation of APE-1 (TG) with OGG-1 (CC). When genotypes were combined by considering only the repair enzymes studied or two by two, it was found that most patients infected with the wild-type of PARP-1 were carriers of the variant allele for at least one of the enzymes and that most patients infected with less pathogenic strains possess a polymorphic allele of APE-1, independent of the genotype associated with the repair enzyme. Taken together, these data indicate the relevance of the APE-1 polymorphism in the development of gastric cancer in individuals infected with less virulent strains and corroborate the importance of the bacterial genotype, since; in general, individuals with wild-type for enzymes repair studied developed gastric cancer when infected with virulent strains.