RESUMO
OBJECTIVE: This study aimed to determine the frequencies of Epstein-Barr virus, types 1 and 2 infection, and 30 bp del-latent membrane protein 1 viral polymorphism in gastric adenocarcinomas, as well as to investigate the association between Epstein-Barr virus infection and tumor location, type, and the patient's sex. METHODS: Samples were collected from 38 patients treated at a university hospital in Rio de Janeiro, Brazil. Epstein-Barr virus detection and genotyping were performed by polymerase chain reaction, followed by polyacrylamide gel electrophoresis and staining by the silver nitrate method. RESULTS: Overall, 68.4% of patients had Epstein-Barr virus-positive tumors. Of these, 65.4% presented infection by Epstein-Barr virus type 1, 23.1% by Epstein-Barr virus type 2, and 11.5% had coinfection with types 1 and 2. The 30 bp del-latent membrane protein 1 polymorphism was found in 42.3% of Epstein-Barr virus-positive tumors, 23.1% had the wild-type virus, and 23.1% had the wild-type and the polymorphism concomitantly. In 11.5% of Epstein-Barr virus-positive tumors, it was impossible to determine whether there was polymorphism or not. Tumor location in the antrum (22 of 38) and diffuse type (27 of 38) were predominant. There was no significant difference in Epstein-Barr virus infection or the 30 bp del-latent membrane protein 1 polymorphism between men and women. CONCLUSION: Epstein-Barr virus infection was found in 68.4% of tumors investigated in this study. To the best of our knowledge, this is the first article showing the coinfection of Epstein-Barr virus types 1 and 2 in gastric carcinoma in Brazil.
Assuntos
Coinfecção , Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Feminino , Humanos , Masculino , Brasil , Herpesvirus Humano 4 , Proteínas de Membrana , Neoplasias Gástricas/virologiaRESUMO
El virus de Epstein-Barr (VEB) fue el primer virus asociado a neoplasias en humanos. Infecta el 95 % de la población mundial, y aunque usualmente es asintomático, puede causar mononucleosis infecciosa y se relaciona con más de 200.000 casos de neoplasias al año. De igual forma, se asocia con esclerosis múltiple y otras enfermedades autoinmunes. A pesar de ser catalogado como un virus oncogénico, solo un pequeño porcentaje de los individuos infectados desarrollan neoplasias asociadas a VEB. Su persistencia involucra la capacidad de alternar entre una serie de programas de latencia, y de reactivarse cuando tiene la necesidad de colonizar nuevas células B de memoria, con el fin de sostener una infección de por vida y poder transmitirse a nuevos hospederos. En esta revisión se presentan las generalidades del VEB, además de su asociación con varios tipos de neoplasias, como son el carcinoma nasofaríngeo, el carcinoma gástrico, el linfoma de Hodgkin y el linfoma de Burkitt, y la esclerosis múltiple. Adicionalmente, se describen los mecanismos fisiopatológicos de las diferentes entidades, algunos de ellos no completamente dilucidados
Epstein-Barr virus (EBV) was the first virus associated with human cancer. It infects 95% of the world's population, and although it is usually asymptomatic, it causes infectious mononucleosis. It is related to more than 200,000 cases of cancer per year, and is also associated with multiple sclerosis and other autoimmune diseases. Despite being classified as an oncogenic virus, only a small percentage of infected individuals develop EBV-associated cancer. Its persistence involves the ability to alternate between a series of latency programs, and the ability to reactivate itself when it needs to colonize new memory B cells, in order to sustain a lifelong infection and be able to transmit to new hosts. In this review, the general characteristics of EBV are presented, in addition to its association with various types of cancers, such as nasopharyngeal carcinoma, gastric carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma, and multiple sclerosis. Additionally, the pathophysiological mechanisms of the different entities are described, some of them not completely elucidated yet
Assuntos
Humanos , Herpesvirus Humano 4/fisiologia , Infecções por Vírus Epstein-Barr/complicações , Neoplasias Gástricas/fisiopatologia , Neoplasias Gástricas/virologia , Doença de Hodgkin/fisiopatologia , Doença de Hodgkin/virologia , Neoplasias Nasofaríngeas/fisiopatologia , Neoplasias Nasofaríngeas/virologia , Linfoma de Burkitt/fisiopatologia , Linfoma de Burkitt/virologia , Carcinogênese , Carcinoma Nasofaríngeo/fisiopatologia , Carcinoma Nasofaríngeo/virologia , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/virologiaRESUMO
The Epstein-Barr virus (EBV) is a well-adapted human virus, and its infection is exclusive to our species, generally beginning in the childhood and then persisting throughout the life of most of the affected adults. Although this infection generally remains asymptomatic, EBV can trigger life-threatening conditions under unclear circumstances. The EBV lifecycle is characterized by interactions with other viruses or bacteria, which increases the probability of awakening its pathobiont capacity. For instance, EBV infects B cells with the potential to alter the germinal center reaction (GCR)-an adaptive immune structure wherein mutagenic-driven processes take place. HIV- and Plasmodium falciparum-induced B cell hyperactivation also feeds the GCR. These agents, along with the B cell tropic KSHV, converge in the ontogeny of germinal center (GC) or post-GC lymphomas. EBV oral transmission facilitates interactions with local bacteria and HPV, thereby increasing the risk of periodontal diseases and head and neck carcinomas. It is less clear as to how EBV is localized in the stomach, but together with Helicobacter pylori, they are known to be responsible for gastric cancer. Perhaps this mechanism is reminiscent of the local inflammation that attracts different herpesviruses and enhances graft damage and chances of rejection in transplanted patients. In this review, we discussed the existing evidence suggestive of EBV possessing the potential to synergize or cooperate with these agents to trigger or worsen the disease.
Assuntos
Coinfecção/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/patogenicidade , Interações entre Hospedeiro e Microrganismos , Animais , Linfócitos B/imunologia , Linfócitos B/virologia , Coinfecção/microbiologia , Coinfecção/parasitologia , Coinfecção/virologia , Infecções por Vírus Epstein-Barr/imunologia , Centro Germinativo/virologia , Helicobacter pylori , Herpesvirus Humano 4/imunologia , Humanos , Camundongos , Neoplasias Gástricas/virologiaRESUMO
BACKGROUND: Colombians in coastal Tumaco have a lower incidence of Helicobacter pylori-associated gastric cancer compared to individuals from Tuquerres in the high Andes. This is despite nearly universal prevalence of H. pylori infection and chronic gastritis. METHODS: H. pylori infection was confirmed by Steiner stain and serology using African and European-origin strains. Gastric histology and serum inflammatory biomarkers in dyspeptic Tumaco or Tuquerres patients were evaluated to predict progression of gastric lesions. RESULTS: H. pylori infection was nearly universal by Steiner stain and serology. IgG response to European-origin H. pylori strains were greater than African-origin. High gastric cancer-risk Tuquerres patients, compared to low-risk Tumaco, had significant odds ratios for lesion progression associated with serum IL-5, trefoil factor 3 (TFF3), and low pepsinogen I/II ratio. Sensitivity and specificity for these parameters was 63.8% and 67.9%, respectively, with correctly classifying patients at 66.7%. Most odds ratios for 26 other biomarkers were significant for the town of residency, indicating an environmental impact on Tumaco patients associated with decreased lesion progression. CONCLUSION: An IL-5 association with progression of gastric lesions is novel and could be evaluated in addition to TFF3 and pepsinogen I/II ratio as a non-invasive prognostic screen. Results suggest Tumaco patients were exposed to infectious diseases beyond H. pylori such as the documented high incidence of helminthiasis and toxoplasmosis. IMPACT: Results support a prior recommendation to evaluate TFF3 and pepsinogen I/II together to predict aggressive gastric histology. Our data indicate IL-5 should be further evaluated as prognostic parameter.
Assuntos
Biomarcadores/sangue , Infecções por Helicobacter/complicações , Helicobacter pylori/isolamento & purificação , Interleucina-5/sangue , Lesões Pré-Cancerosas/epidemiologia , Neoplasias Gástricas/epidemiologia , Fator Trefoil-3/sangue , Adulto , Estudos de Casos e Controles , Colômbia/epidemiologia , Feminino , Infecções por Helicobacter/virologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/sangue , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/virologia , Neoplasias Gástricas/sangue , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologiaRESUMO
BACKGROUND: Gastric cancer (GC) has been defined in distinct molecular subtypes with different therapeutic implications. However, its clinical significance and prognosis regarding standard chemotherapy (CMT) remains unclear. This study aimed to analyze the impact of perioperative or adjuvant treatment among subtypes of GC. METHODS: We retrospectively evaluated all stage II/III patients with GC who underwent a curative gastrectomy. Based on immunohistochemistry and in situ hybridization techniques, GC was classified into five subtypes: Epstein-Barr virus (EBV) positive, microsatellite instability (MSI), e-cadherin aberrant, p53-aberrant, and p53-normal. RESULTS: Among the 178 CG included, 111 patients received CMT and 67 were treated with surgery alone. Survival analysis showed that p53-aberrant GC treated with CMT had better disease-free survival (DFS) compared with surgery alone (P = .001).There was no significant difference in DFS between patients who received CMT and those with surgery alone for EBV, MSI, E-cadherin, and p53-normal GC. An improvement in overall survival was observed only for E-cadherin (P = .001) and p53-aberrant (P < .001) patients who received CMT. CONCLUSIONS: CMT showed different impact on the survival of CG according to the molecular subtype. No survival benefit was observed for EBV and MSI groups who received CMT. GC with p53-aberrant had a significant benefit in survival with standard therapy.
Assuntos
Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/terapia , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Adenocarcinoma/virologia , Antígenos CD/metabolismo , Caderinas/metabolismo , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Gastrectomia , Herpesvirus Humano 4 , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/virologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
Mechanisms of viral oncogenesis are diverse and include the off-target activity of enzymes expressed by the infected cells, which evolved to target viral genomes for controlling their infection. Among these enzymes, the single-strand DNA editing capability of APOBECs represent a well-conserved viral infection response that can also cause untoward mutations in the host DNA. Here we show, after evaluating somatic single-nucleotide variations and transcriptome data in 240 gastric cancer samples, a positive correlation between APOBEC3s mRNA-expression and the APOBEC-mutation signature, both increased in EBV+ tumors. The correlation was reinforced by the observation of APOBEC mutations preferentially occurring in the genomic loci of the most active transcripts. This EBV infection and APOBEC3 mutation-signature axis were confirmed in a validation cohort of 112 gastric cancer patients. Our findings suggest that APOBEC3 upregulation in EBV+ cancer may boost the mutation load, providing further clues to the mechanisms of EBV-induced gastric carcinogenesis. After further validation, this EBV-APOBEC axis may prove to be a secondary driving force in the mutational evolution of EBV+ gastric tumors, whose consequences in terms of prognosis and treatment implications should be vetted.
Assuntos
Citidina Desaminase/genética , DNA de Neoplasias/genética , Herpesvirus Humano 4/patogenicidade , Neoplasias Gástricas/virologia , Desaminases APOBEC , Carcinogênese , Genes Virais , Herpesvirus Humano 4/genética , Humanos , Mutação , Neoplasias Gástricas/patologiaRESUMO
El virus de Epstein Barr (VEB) es responsable del 10% del cáncer gástrico (CG) y se correlaciona con mejor tasa de sobrevida. En Perú, no existen estudios sobre prevalencia y características clínicas de CG VEB positivo. Objetivos: Determinar la prevalencia y las características clínico patológicas del CG VEB positivo. Materiales y métodos: 111 muestras de GC fueron examinadas centralmente por hibridización cromogénica in situ del RNA del VEB (EBER CISH). Resultados: El 8,4% de los casos fueron positivos para VEB. La mayoría de los casos VEB positivos tuvieron más de 60 años, varones y la localización, antro / píloro fue la más frecuente. La mayoría de los casos fueron de tipo intestinal y un patrón tubular con una tendencia a un mejor pronóstico en comparación con los casos de VEB negativo. Conclusión: CG VEB positivo es una entidad con una prevalencia de 8,4% en Perú con características clínicas y morfológicas distintivas.
Epstein Barr Virus (EBV) is responsible of 10% of Gastric Cancer (GC), correlating with better survival rates. In Peru, there were not studies about prevalence and clinical characteristics of CG EBV positive. Objective: Determine prevalence and clinicopathological characteristics of GC EBV positive. Materials and methods: 111 GC tumour samples were centrally screened by Chromogenic in situ hybridization (CISH) technique for EBV-encoded RNA (EBER) transcript. Results: 8.4% of cases were positive for EBV. Most cases EBV positive were more than 60 years old; male, antrum/pylorus had more frequent localizations. Most cases had an intestinal type and tubular patter and a tendency to better prognostic in comparison EBV negative cases. Conclusion: EBV positive GC is an entity with a prevalence of 8.4% in Peru with distinctive clinical and morphological characteristics.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/virologia , Herpesvirus Humano 4 , Infecções por Vírus Epstein-Barr/complicações , Peru/epidemiologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/epidemiologia , Prevalência , Estudos Retrospectivos , Distribuição por Sexo , Distribuição por Idade , Infecções por Vírus Epstein-Barr/epidemiologiaRESUMO
OBJECTIVE: to compare the polymorphism of the Glutathione S-transferase theta 1 (GSTT1) and Glutathione S-transferase mu 1 (GSTM1) genes from the tumor area with the proximal and distal margins of stomach specimens resected from patients with gastric cancer, and to investigate the presence of Epstein-Barr virus (EBV) DNA and Helicobacter pylori. METHODS: we prospectively collected tissue specimens from the tumor area and from the proximal and distal resection margins of the stomachs of ten patients with gastric adenocarcinoma who underwent gastrectomy with D2 lymphadenectomy, and submitted these specimens to DNA extraction. We compared the tumor area with the proximal and distal margins of the resected stomachs for polymorphism of GSTT1 and GSTM1 genes and investigated the presence of EBV-DNA and H. pylori. We used the p53 exon 5 gene as an internal control of the multiplex PCR reaction. RESULTS: in one patient, we detected null GSTT1 and GSTM1 genotypes in the tumor area, in contrast to the presence of both genes in the proximal and distal margins. We found EBV-DNA and H. pylori in the tumor area and also in the proximal and distal margins. In another patient, the proximal margin was negative for GSTT1, and EBV-DNA was negative in the distal margin. In three patients, EBV-DNA was negative only in the distal margin. CONCLUSION: this is the first report where different genotypes, EBV-DNA and H. pylori infection were observed in the same patient, indicating a probable deletion of these genes in response to tumor progression and intratumoral heterogeneity.
OBJETIVO: comparar o polimorfismo dos genes Glutationa S-transferase teta 1 (GSTT1) e Glutationa S-transferase mu 1 (GSTM1) da área do tumor com as margens proximal e distal de espécimes de estômago ressecados de pacientes com câncer gástrico, e investigar a presença do DNA do vírus Epstein-Barr (EBV) e Helicobacter pylori. MÉTODOS: coletamos prospectivamente amostras teciduais da área do tumor e das margens de ressecção proximal e distal dos estômagos de dez pacientes com adenocarcinoma gástrico submetidos à gastrectomia com linfadenectomia D2 e submetemos esses espécimes à extração de DNA. Comparamos a área do tumor com as margens proximal e distal dos estômagos ressecados para o polimorfismo dos genes GSTT1 e GSTM1 e investigamos a presença de DNA do EBV e H. pylori. Utilizamos o exon 5 do gene p53 como controle interno da reação de PCR multiplex. RESULTADOS: em um paciente, detectamos genótipos GSTT1 e GSTM1 nulos na área do tumor, em contraste com a presença de ambos os genes nas margens proximal e distal. Encontramos DNA do EBV e H. pylori na área do tumor e também nas margens proximal e distal. Em outro paciente, a margem proximal foi negativa para GSTT1 e o DNA do EBV foi negativo na margem distal. Em três pacientes, o EBV-DNA foi negativo apenas na margem distal. CONCLUSÃO: este é o primeiro relato em que diferentes genótipos, infecção por EBV-DNA e H. pylori foram observados no mesmo paciente, indicando provável deleção desses genes em resposta à progressão tumoral e heterogeneidade intratumoral.
Assuntos
Adenocarcinoma/cirurgia , Helicobacter pylori/genética , Herpesvirus Humano 4/genética , Polimorfismo Genético/genética , Neoplasias Gástricas/cirurgia , Adenocarcinoma/enzimologia , Adenocarcinoma/microbiologia , Adenocarcinoma/virologia , Idoso , Feminino , Genótipo , Glutationa Transferase/genética , Helicobacter pylori/isolamento & purificação , Herpesvirus Humano 4/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/virologiaRESUMO
Epstein Barr Virus (EBV) is responsible of 10% of Gastric Cancer (GC), correlating with better survival rates. In Peru, there were not studies about prevalence and clinical characteristics of CG EBV positive. OBJECTIVE: Determine prevalence and clinicopathological characteristics of GC EBV positive. MATERIALS AND METHODS: 111 GC tumour samples were centrally screened by Chromogenic in situ hybridization (CISH) technique for EBV-encoded RNA (EBER) transcript. RESULTS: 8.4% of cases were positive for EBV. Most cases EBV positive were more than 60 years old; male, antrum/pylorus had more frequent localizations. Most cases had an intestinal type and tubular patter and a tendency to better prognostic in comparison EBV negative cases. CONCLUSION: EBV positive GC is an entity with a prevalence of 8.4% in Peru with distinctive clinical and morphological characteristics.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Neoplasias Gástricas/virologia , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Infecções por Vírus Epstein-Barr/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peru/epidemiologia , Prevalência , Estudos Retrospectivos , Distribuição por Sexo , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologiaRESUMO
RESUMO Objetivo: comparar o polimorfismo dos genes Glutationa S-transferase teta 1 (GSTT1) e Glutationa S-transferase mu 1 (GSTM1) da área do tumor com as margens proximal e distal de espécimes de estômago ressecados de pacientes com câncer gástrico, e investigar a presença do DNA do vírus Epstein-Barr (EBV) e Helicobacter pylori. Métodos: coletamos prospectivamente amostras teciduais da área do tumor e das margens de ressecção proximal e distal dos estômagos de dez pacientes com adenocarcinoma gástrico submetidos à gastrectomia com linfadenectomia D2 e submetemos esses espécimes à extração de DNA. Comparamos a área do tumor com as margens proximal e distal dos estômagos ressecados para o polimorfismo dos genes GSTT1 e GSTM1 e investigamos a presença de DNA do EBV e H. pylori. Utilizamos o exon 5 do gene p53 como controle interno da reação de PCR multiplex. Resultados: em um paciente, detectamos genótipos GSTT1 e GSTM1 nulos na área do tumor, em contraste com a presença de ambos os genes nas margens proximal e distal. Encontramos DNA do EBV e H. pylori na área do tumor e também nas margens proximal e distal. Em outro paciente, a margem proximal foi negativa para GSTT1 e o DNA do EBV foi negativo na margem distal. Em três pacientes, o EBV-DNA foi negativo apenas na margem distal. Conclusão: este é o primeiro relato em que diferentes genótipos, infecção por EBV-DNA e H. pylori foram observados no mesmo paciente, indicando provável deleção desses genes em resposta à progressão tumoral e heterogeneidade intratumoral.
ABSTRACT Objective: to compare the polymorphism of the Glutathione S-transferase theta 1 (GSTT1) and Glutathione S-transferase mu 1 (GSTM1) genes from the tumor area with the proximal and distal margins of stomach specimens resected from patients with gastric cancer, and to investigate the presence of Epstein-Barr virus (EBV) DNA and Helicobacter pylori. Methods: we prospectively collected tissue specimens from the tumor area and from the proximal and distal resection margins of the stomachs of ten patients with gastric adenocarcinoma who underwent gastrectomy with D2 lymphadenectomy, and submitted these specimens to DNA extraction. We compared the tumor area with the proximal and distal margins of the resected stomachs for polymorphism of GSTT1 and GSTM1 genes and investigated the presence of EBV-DNA and H. pylori. We used the p53 exon 5 gene as an internal control of the multiplex PCR reaction. Results: in one patient, we detected null GSTT1 and GSTM1 genotypes in the tumor area, in contrast to the presence of both genes in the proximal and distal margins. We found EBV-DNA and H. pylori in the tumor area and also in the proximal and distal margins. In another patient, the proximal margin was negative for GSTT1, and EBV-DNA was negative in the distal margin. In three patients, EBV-DNA was negative only in the distal margin. Conclusion: this is the first report where different genotypes, EBV-DNA and H. pylori infection were observed in the same patient, indicating a probable deletion of these genes in response to tumor progression and intratumoral heterogeneity.