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E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients

Oliveira, Carla; Ferreira, Paulo; Nabais, Sérgio; Campos, Luísa; Ferreira, Ana; Cirnes, Luís; Alves, Catarina Castro; Veiga, Isabel; Fragoso, Maria; Regateiro, Fernando; Dias, Luís Moreira; Moreira, Herculano; Suriano, Gianpaolo; Machado, José Carlos
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Artigo de Revista Científica Formato: aplication/PDF
ENG
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Approximately 30% of all hereditary diffuse gastric cancer (HDGC) families carry CDH1 germline mutations. The other two thirds remain genetically unexplained and are probably caused by alterations in other genes. Using polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP)/sequencing, we screened 32 Portuguese families with a history of gastric cancer and 23 patients with early onset gastric cancer for CDH1 germline mutations. In probands negative for CDH1 mutations, we screened genes involved in hereditary cancer syndromes in which gastric cancer may be one of the component tumours, namely p53 (Li-Fraumeni Syndrome) and hMLH1 and hMSH2 (HNPCC). We also screened in these patients for mutations in Caspase-10, a gene inactivated in sporadic gastric cancer, and SMAD4, a gene whose inactivation in mice is associated with signet-ring cell carcinoma of the stomach. One of the families fulfilling the HDGC criteria harboured a CDH1 germline mutation, and one of the families with incomplete criteria harboured a p53 germline mutation. No mutations were identified in hMLH1 and hMSH2, and only sequence variants were found in SMAD4 and Caspase-10. The present work reports for the first time CDH1 germline mutations in Portuguese gastric cancer families...

Methylation status of ANAPC1, CDKN2A and TP53 promoter genes in individuals with gastric cancer

LIMA, E.M.; LEAL, M.F.; BURBANO, R.R.; KHAYAT, A.S.; ASSUMPÇÃO, P.P.; BELLO, M.J.; REY, J.A.; SMITH, M.A.C.; CASARTELLI, C.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica
ENG
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66.24%
Gastric cancer is the forth most frequent malignancy and the second most common cause of cancer death worldwide. DNA methylation is the most studied epigenetic alteration, occurring through a methyl radical addition to the cytosine base adjacent to guanine. Many tumor genes are inactivated by DNA methylation in gastric cancer. We evaluated the DNA methylation status of ANAPC1, CDKN2A and TP53 by methylation-specific PCR in 20 diffuse- and 26 intestinal-type gastric cancer samples and 20 normal gastric mucosa in individuals from Northern Brazil. All gastric cancer samples were advanced stage adenocarcinomas. Gastric samples were surgically obtained at the João de Barros Barreto University Hospital, State of Pará, and were stored at -80°C before DNA extraction. Patients had never been submitted to chemotherapy or radiotherapy, nor did they have any other diagnosed cancer. None of the gastric cancer samples presented methylated DNA sequences for ANAPC1 and TP53. CDKN2A methylation was not detected in any normal gastric mucosa; however, the CDKN2A promoter was methylated in 30.4% of gastric cancer samples, with 35% methylation in diffuse-type and 26.9% in intestinal-type cancers. CDKN2A methylation was associated with the carcinogenesis process for ~30% diffuse-type and intestinal-type compared to non-neoplastic samples. Thus...

DNA mismatch repair gene methylation in gastric cancer in individuals from northern Brazil

LIMA, Eleonidas Moura; LEAL, Mariana Ferreira; SMITH, Marilia de Arruda Cardoso; BURBANO, Rommel Rodriguez; ASSUMPCAO, Paulo Pimentel de; BELLO, Maria Jose; REY, Juan Antonio; LIMA, Francinaldo Ferreira de; CASARTELLI, Cacilda
Fonte: INST HISTOL EMBRIOL-CONICET Publicador: INST HISTOL EMBRIOL-CONICET
Tipo: Artigo de Revista Científica
ENG
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Gastric cancer is one of the most common malignancies. DNA methylation is implicated in DNA mismatch repair genes deficiency. In the present study, we evaluated the methylation status of MLH1, MSH2, MSH6 and PMS2 in 20 diffuse- and 26 intestinal-type gastric cancer samples and 20 normal gastric mucosal of gastric cancer patients from Northern Brazil. We found that none of the nonneoplastic samples showed methylation of any gene promoter and 50% of gastric, cancer samples showed at least one methylated gene promoter. Methylation frequencies of MLH1, MSH2, MSH6 and PMS2 promoter were 21.74%, 17.39%, 0% and 28.26% respectively in gastric cancer samples. MLH1 and PMS2 methylation were associated with neoplastic samples compared to nonneoplastic ones. PMS2:? methylation was associated with diffuse- and intestinal-type cancer compared with normal controls. Intestinal-type cancer showed significant association with MLH1 methylation. Diffuse-type cancer was significantly associated with MSH2 methylation. Our findings show differential gene methylation in tumoral tissue, which allows us to conclude that methylation is associated with gastric carcinogenesis. Methylation of mismatch repair genes was associated with gastric carcinogenesis and may be a helpful tool for diagnosis...

MYC, FBXW7 and TP53 copy number variation and expression in gastric cancer

Calcagno, Danielle Queiroz; Freitas, Vanessa Morais; Leal, Mariana Ferreira; Souza, Carolina Rosal Teixeira de; Demachki, Samia; Montenegro, Raquel; Assumpção, Paulo Pimentel; Khayat, André Salim; Smith, Marília de Arruda Cardoso; Santos, Andrea Kelly
Fonte: BioMed Central; London Publicador: BioMed Central; London
Tipo: Artigo de Revista Científica
ENG
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BACKGROUND: MYC deregulation is a common event in gastric carcinogenesis, usually as a consequence of gene amplification, chromosomal translocations, or posttranslational mechanisms. FBXW7 is a p53-controlled tumor-suppressor that plays a role in the regulation of cell cycle exit and reentry via MYC degradation. METHODS: We evaluated MYC, FBXW7, and TP53 copy number, mRNA levels, and protein expression in gastric cancer and paired non-neoplastic specimens from 33 patients and also in gastric adenocarcinoma cell lines. We also determined the invasion potential of the gastric cancer cell lines. RESULTS: MYC amplification was observed in 51.5% of gastric tumor samples. Deletion of one copy of FBXW7 and TP53 was observed in 45.5% and 21.2% of gastric tumors, respectively. MYC mRNA expression was significantly higher in tumors than in non-neoplastic samples. FBXW7 and TP53 mRNA expression was markedly lower in tumors than in paired non-neoplastic specimens. Moreover, deregulated MYC and FBXW7 mRNA expression was associated with the presence of lymph node metastasis and tumor stage III-IV. Additionally, MYC immunostaining was more frequently observed in intestinal-type than diffuse-type gastric cancers and was associated with MYC mRNA expression. In vitro studies showed that increased MYC and reduced FBXW7 expression is associated with a more invasive phenotype in gastric cancer cell lines. This result encouraged us to investigate the activity of the gelatinases MMP-2 and MMP-9 in both cell lines. Both gelatinases are synthesized predominantly by stromal cells rather than cancer cells...

Imunoexpressão da E-caderina, Beta-catenina e TP53 em câncer gástrico familial; Imunoexpression of E-cadherin, Beta-catenin and TP53 in familial gastric cancer

Bambino, Paula Balthazar
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 03/06/2009 PT
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Introdução: Agregação familial é observada em cerca de 10% dos casos de câncer e 1 a 3% é hereditário. O tipo difuso pode estar relacionado à agregação familial e a alterações genéticas no gene CDH1, que codifica a proteína E-caderina. Alterações na imunoexpressão de Beta-catenina e p53 também são observadas. Objetivos: Analisar a imunoexpressão da E-caderina, Beta-catenina e TP53 em adenocarcinomas gástricos de pacientes com câncer gástrico familial e comparar com os dados clinicopatológicos, além dos achados das alterações genéticas destes pacientes, estudadas previamente nesta Instituição. Casuística e Métodos: Vinte e seis casos de adenocarcinoma gástrico em blocos de parafina de pacientes do HC-FMUSP foram submetidos ao estudo imunoistoquímico para detecção e análise do padrão de imunoexpressão da E-caderina, Beta-catenina e TP53 através do método da streptavidina-biotina-peroxidase. A análise da imunoexpressão dos marcadores foi classificada segundo escala de intensidade e distribuição e os testes estatísticos utilizados foram o Teste t de Student e Exato de Fisher. Resultados: A localização predominante do tumor foi no antro (61,5%). 11 (42,3%) casos alterados para a imunoexpressão da E-caderina...

Profiles of gene polymorphisms in cytokines and toll-like receptors with higher risk for gastric cancer

De Oliveira, Juliana Garcia; Rossi, Ana Flávia Teixeira; Nizato, Daniela Manchini; Miyasaki, Kenji; Silva, Ana Elizabete
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 978-988
ENG
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Background: Chronic inflammation and gastric carcinogenesis show a close association, so gene polymorphisms that modify the intensity of the inflammatory response may contribute to variations in gastric cancer risk. Aims: The purpose of this study was to investigate the combined effect of the pro- and anti-inflammatory cytokines and toll-like receptors polymorphisms on the chronic gastritis and gastric cancer risk in a Brazilian population sample. Methods: We evaluated 669 DNA samples (200 of gastric cancer [GC], 229 of chronic gastritis [CG], and 240 of healthy individuals [C]). Ten polymorphisms were genotyped: IL-1RN and TLR2 -196 to -174 del using the allele-specific PCR method and TNF-A (rs1800629; rs1799724), TNF-B (rs909253), IL-8 (rs4073; rs2227532), IL-10 (rs1800872) and TLR4 (rs4986790; rs4986791) using PCR-RFLP. Results: Polymorphisms TNF-A-308G/A, IL-8-251A/T, TNF-B + 252A/G and TLR4 + 1196C/T were not associated with risk of any gastric lesion. However, an association with increased risk for GC was observed for polymorphisms IL-1RNL/2 (p < 0.001), TNF-A-857C/T (p = 0.022), IL-8-845T/C (p < 0.001), IL-10-592C/A (p < 0.001), TLR2ins/del (p < 0.001), and TLR4 + 896A/G (p = 0.033). In CG, an association was observed only with polymorphisms IL-1RNL/2 and IL-10-592A/C (p < 0.001 for both). A combined analysis of these six polymorphisms associated with GC revealed a profile with two to four combined genotypes which confer a higher risk of gastric carcinogenesis...

Association between EGF +61A/G polymorphism and gastric cancer in Caucasians

Araújo, Ana Paula; Costa, Bruno Marques; Correia, Ana L. Pinto; Fragoso, Maria; Ferreira, Paula; Ribeiro, Mário Dinis; Costa, Sandra Maria Araújo da; Reis, R. M.; Medeiros, Rui
Fonte: Baishideng Publicador: Baishideng
Tipo: Artigo de Revista Científica
Publicado em 28/01/2011 ENG
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To investigate the association between epidermal growth factor (EGF) +61A/G polymorphism and susceptibility to gastric cancer, through a cross-sectional study. METHODS: Polymerase chain reaction resctriction fragment lenght polymorphism analyses were used to genotype EGF +61 in 207 patients with gastric lesions (162 patients with gastric adenocarcinomas, 45 with atrophy or intestinal metaplasia) and 984 controls. All subjects were Caucasian. RESULTS: Genotype distribution was 23.5% for GG and 76.5% for GA/AA in the control group, 18.4% for GG and 68.6% for GA/AA in the entire group with gastric lesions and 17.9% for GG and 82.1% for GA/AA in the group with gastric adenocarcinoma. No statistically significant associations were found between EGF +61 variants and risk for developing gastric cancer [odds ratios (OR) = 1.41, 95% confidence intervals (CI): 0.90-2.21, P = 0.116]. However, the stratification of individuals by gender revealed that males carrying A alleles (EGF +61A/G or AA) had an increased risk for developing gastric cancer as compared to GG homozygous males (OR = 1.55, 95% CI: 1.05-2.28, P = 0.021). CONCLUSION: In summary, we found that males who were A carriers for EGF +61 had an increased risk for developing gastric cancer. This result may be explained by the suggestion that women secrete less gastric acid than men.; The Portuguese League Against Cancer (Liga Portuguesa Contra o Cancro-Núcleo Regional do Norte); AstraZeneca Foundation

-765 G>C POLYMORPHISM OF THE COX-2 GENE AND GASTRIC CANCER RISK IN BRAZILIAN POPULATION

CAMPANHOLO,Vanessa Maria de Lima Pazine; FELIPE,Aledson Vitor; LIMA,Jacqueline Miranda de; PIMENTA,Célia Aparecida Marques; VENTURA,Rogéria Maria; FORONES,Nora Manoukian
Fonte: Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia - IBEPEGE ; Colégio Brasileiro de Cirurgia Digestiva - CBCD ; Sociedade Brasileira de Motilidade Digestiva - SBMD ; Federação Brasileira de Gastroenterologia - FBG; Sociedade Brasileira de Hepatologia - SBH; Sociedade Brasileira de Endoscopia Digestiva - SOBED Publicador: Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia - IBEPEGE ; Colégio Brasileiro de Cirurgia Digestiva - CBCD ; Sociedade Brasileira de Motilidade Digestiva - SBMD ; Federação Brasileira de Gastroenterologia - FBG; Sociedade Brasileira de Hepatologia - SBH; Sociedade Brasileira de Endoscopia Digestiva - SOBED
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2014 EN
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Context Genomic alterations play important roles in gastric cancer carcinogenesis. Cyclooxygenases (COX) are important enzymes in the maintenance of mucosal integrity and in pathological processes, mainly in inflammation and cancer. The -765G>C COX-2 polymorphism has been implicated in gastric cancer risk. Objectives To evaluate the COX-2 gene polymorphism as a predictor of gastric cancer risk. Methods One hundred gastric cancer patients and 150 controls were enrolled from a Brazilian centre. Personal data regarding related risk factors, including alcohol consumption and smoking behavior, were collected via questionnaire. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR-restriction fragment length polymorphism. Results G/G, G/C and C/C genotypes frequencies was 42.7%, 50% and 7.3%, respectively in controls and 59.0%, 34.0% and 7.0% in gastric cancer. The frequency of the genotypes differed between the groups (P = 0.033). A higher risk of gastric cancer was associated with COX-2 -765G/G genotype (P = 0.048; OR:1.98, 95% CI = 1.01-3.90). Alcohol consumption and smoking in patients with -765G/G genotype also increased the risk of gastric cancer. Conclusions The -765G/G genotype and the -765G allele had been associated with an increased risk for gastric cancer. The presence of smoking and alcohol consumption increased the risk for gastric cancer in subjects with -765G/G genotype compared with the control group. Polymorphism of COX-2 gene and gastric cancer risk.

Methylation status of ANAPC1, CDKN2A and TP53 promoter genes in individuals with gastric cancer

Lima,E.M.; Leal,M.F.; Burbano,R.R.; Khayat,A.S.; Assumpção,P.P.; Bello,M.J.; Rey,J.A.; Smith,M.A.C.; Casartelli,C.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2008 EN
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66.24%
Gastric cancer is the forth most frequent malignancy and the second most common cause of cancer death worldwide. DNA methylation is the most studied epigenetic alteration, occurring through a methyl radical addition to the cytosine base adjacent to guanine. Many tumor genes are inactivated by DNA methylation in gastric cancer. We evaluated the DNA methylation status of ANAPC1, CDKN2A and TP53 by methylation-specific PCR in 20 diffuse- and 26 intestinal-type gastric cancer samples and 20 normal gastric mucosa in individuals from Northern Brazil. All gastric cancer samples were advanced stage adenocarcinomas. Gastric samples were surgically obtained at the João de Barros Barreto University Hospital, State of Pará, and were stored at -80°C before DNA extraction. Patients had never been submitted to chemotherapy or radiotherapy, nor did they have any other diagnosed cancer. None of the gastric cancer samples presented methylated DNA sequences for ANAPC1 and TP53. CDKN2A methylation was not detected in any normal gastric mucosa; however, the CDKN2A promoter was methylated in 30.4% of gastric cancer samples, with 35% methylation in diffuse-type and 26.9% in intestinal-type cancers. CDKN2A methylation was associated with the carcinogenesis process for ~30% diffuse-type and intestinal-type compared to non-neoplastic samples. Thus...

Cytogenetic characterization and evaluation of c-MYC gene amplification in PG100, a new Brazilian gastric cancer cell line

Ribeiro,H.F.; Alcântara,D.F.A.; Matos,L.A.; Sousa,J.M.C.; Leal,M.F.; Smith,M.A.C.; Burbano,R.R.; Bahia,M.O.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/08/2010 EN
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Gastric cancer is the fourth most frequent type of cancer and the second cause of cancer mortality worldwide. The genetic alterations described so far for gastric carcinomas include amplifications and mutations of the c-ERBB2, KRAS, MET, TP53, and c-MYC genes. Chromosomal instability described for gastric cancer includes gains and losses of whole chromosomes or parts of them and these events might lead to oncogene overexpression, showing the need for a better understanding of the cytogenetic aspects of this neoplasia. Very few gastric carcinoma cell lines have been isolated. The establishment and characterization of the biological properties of gastric cancer cell lines is a powerful tool to gather information about the evolution of this malignancy, and also to test new therapeutic approaches. The present study characterized cytogenetically PG-100, the first commercially available gastric cancer cell line derived from a Brazilian patient who had a gastric adenocarcinoma, using GTG banding and fluorescent in situ hybridization to determine MYC amplification. Twenty metaphases were karyotyped; 19 (95%) of them presented chromosome 8 trisomy, where the MYC gene is located, and 17 (85%) presented a deletion in the 17p region, where the TP53 is located. These are common findings for gastric carcinomas...

Serum metabolic profiling of human gastric cancer based on gas chromatography/mass spectrometry

Song,Hu; Peng,Jun-Sheng; Dong-Sheng,Yao; Yang,Zu-Li; Liu,Huan-Liang; Zeng,Yi-Ke; Shi,Xian-Ping; Lu,Bi-Yan
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2012 EN
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Research on molecular mechanisms of carcinogenesis plays an important role in diagnosing and treating gastric cancer. Metabolic profiling may offer the opportunity to understand the molecular mechanism of carcinogenesis and help to non-invasively identify the potential biomarkers for the early diagnosis of human gastric cancer. The aims of this study were to explore the underlying metabolic mechanisms of gastric cancer and to identify biomarkers associated with morbidity. Gas chromatography/mass spectrometry (GC/MS) was used to analyze the serum metabolites of 30 Chinese gastric cancer patients and 30 healthy controls. Diagnostic models for gastric cancer were constructed using orthogonal partial least squares discriminant analysis (OPLS-DA). Acquired metabolomic data were analyzed by the nonparametric Wilcoxon test to find serum metabolic biomarkers for gastric cancer. The OPLS-DA model showed adequate discrimination between cancer and non-cancer cohorts while the model failed to discriminate different pathological stages (I-IV) of gastric cancer patients. A total of 44 endogenous metabolites such as amino acids, organic acids, carbohydrates, fatty acids, and steroids were detected, of which 18 differential metabolites were identified with significant differences. A total of 13 variables were obtained for their greatest contribution in the discriminating OPLS-DA model [variable importance in the projection (VIP) value >1.0]...

Update of Adjuvant Chemotherapy for Resected Gastric Cancer

Oh, Sang Cheul
Fonte: The Korean Gastric Cancer Association Publicador: The Korean Gastric Cancer Association
Tipo: Artigo de Revista Científica
EN
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Gastric cancer is the second cause of cancer that is related to death and the fourth most common cancer, worldwide. Complete resection of cancer is the only curative treatment for gastric cancer. However, even if complete resection is possible, recurrence is frequently observed in Gastric patients. Therefore, adjuvant treatment modality for resectable gastric cancer is needed to increase the survival of patients. This study wants to describe the role of adjuvant chemotherapy for resectable gastric cancer, with updated data of recent studies. Several meta-analysis studies demonstrated a benefit of adjuvant chemotherapy for resectable gastric cancer. Due to the heterogeneity of the population and regimens, there is no consensus regarding the adjuvant chemotherapy. Recently published, well designed phase III studies demonstrated the statistically significance of adjuvant chemotherapy for the resectable gastric cancer, with the extended lymph node dissection. Further phase III trials, to determine the best regimen and schedule of adjuvant chemotherapy, was suggested to use the fluoropyrimidine based regimen as control group.

Molecular Diagnosis for Personalized Target Therapy in Gastric Cancer

Cho, Jae Yong
Fonte: The Korean Gastric Cancer Association Publicador: The Korean Gastric Cancer Association
Tipo: Artigo de Revista Científica
EN
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66.24%
Gastric cancer is the second leading cause of cancer-related deaths worldwide. In advanced and metastatic gastric cancer, the conventional chemotherapy with limited efficacy shows an overall survival period of about 10 months. Patient specific and effective treatments known as personalized cancer therapy is of significant importance. Advances in high-throughput technologies such as microarray and next generation sequencing for genes, protein expression profiles and oncogenic signaling pathways have reinforced the discovery of treatment targets and personalized treatments. However, there are numerous challenges from cancer target discoveries to practical clinical benefits. Although there is a flood of biomarkers and target agents, only a minority of patients are tested and treated accordingly. Numerous molecular target agents have been under investigation for gastric cancer. Currently, targets for gastric cancer include the epidermal growth factor receptor family, mesenchymal-epithelial transition factor axis, and the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathways. Deeper insights of molecular characteristics for gastric cancer has enabled the molecular classification of gastric cancer, the diagnosis of gastric cancer...

Gastric Cancer in Individuals with Li-Fraumeni Syndrome

Masciari, Serena; Dewanwala, Akriti; Stoffel, Elena M.; Lauwers, Gregory Y.; Hui, Hui; Achatz, Maria Isabel; Riegert-Johnson, Douglas; Foretova, Lenka; Silva, Edaise M.; Digianni, Lisa; Verselis, Sigitas J.; Schneider, Katherine; Li, Frederick Pei; Fraume
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN_US
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PURPOSE: Li-Fraumeni syndrome is a rare hereditary cancer syndrome associated with germline mutations in the TP53 gene. Although sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as Li-Fraumeni syndrome-associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer in Li-Fraumeni syndrome. METHODS: Pedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute Li-Fraumeni syndrome registry. We identified subjects with gastric cancer documented either by pathology report or death certificate and performed pathology review of the available specimens. RESULTS: Among 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. Gastric cancer was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at gastric cancer diagnosis were 43 and 36 years, respectively (range: 24-74 years), significantly younger compared with the median age at diagnosis in the general population based on Surveillance Epidemiology and End Results data (71 years). Five (8.1%) families reported two or more cases of gastric cancer...

Lymphangiogenesis in Gastric Cancer regulated through Akt/mTOR-VEGF-C/VEGF-D axis

Chen, Hongxia; Guan, Runnian; Lei, Yupeng; Chen, Jianyong; Ge, Qi; Zhang, Xiaoshen; Dou, Ruoxu; Chen, Hongyuan; Liu, Hao; Qi, Xiaolong; Zhou, Xiaodong; Chen, Changyan
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN_US
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Background: Lymphangiogenesis plays a significant role in metastasis and recurrence of gastric cancer. There is no report yet focusing on the modulation of VEGF pathway and lymphangiogenesis of gastric cancer by targeting Akt/mTOR pathway. This study aims to demonstrate the relationship between Akt/mTOR pathway and VEGF-C/-D in gastric cancer. Methods: We collected surgically resected gastric adenocarcinoma specimens from 55 consented patients. Immunohistochemistry staining of p-Akt, p-mTOR, VEGF-C, VEGF-D were performed and scored by two independent pathologists. The results were presented as staining intensity and positive staining cell rate. We also measured lymphatic vessel density (LVD) by D2-40 staining. Different dosages of p-Akt inhibitor LY294002 (12.5 μM, 25 μM, 50 μM) and p-mTOR inhibitor Rapamycin (25 nM, 50 nM, 100 nM) were given to gastric cancer cell line SGC-7901 in vitro. The inhibition rate of cell growth was tested by MTT at 24 h, 48 h and 72 h, respectively and protein expressions of Akt, p-Akt, mTOR, p-mTOR, VEGF-C and VEGF-D were examined by Western blot. Results: The positive staining rates of p-Akt, p-mTOR, VEGF-C and VEGF-D in 55 gastric cancer clinical specimens were 74.54%, 85.45%, 72.73% and 58.18%. p-Akt and p-mTOR were positively correlated with VEGF-C and VEGF-D (p < 0.01). The LVD increased with incremental tendency of staining intensity of p-Akt...

The role of Krüppel-Like Factor 4 in Human Gastric Cancer Development and Progression and Comparison of the context dependent role of KLF4 and KLF5 in carcinogenesis; Einfluss von Krüppel-Like Factor 4 auf die Entwicklung und Progression des Magenkarzinoms sowie Vergleich der unterschiedlichen Funktionen von KLF4 und KLF5 in der Karzinogese

Schlunk, Christian
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
EN
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The work presented in this thesis, which is based on our publication in Cancer Research in 2005: “Drastic Down-regulation of Krüppel-Like Factor 4 Expression Is Critical in Human Gastric Cancer Development and Progression” provides new insights of the role of KLF4 in human gastric cancer. First, we discovered the distinct KLF4 expression patterns in normal gastric and gastric tumor tissues. Specifically, we found that KLF4 protein was expressed in the cytoplasm and nuclei of cells localized predominantly in the glandular epithelium (glandular differentiation), suggesting that KLF4 plays an important role in the homeostasis and maintenance of gastric mucosa. In contrast, we observed a substantially decreased or lost KLF4 expression in both gastric tumor specimens and tumor cell lines. Second, restored expression of KLF4 significantly inhibited gastric cancer growth in vitro and tumorigenicity in animal models. Third, mechanism study showed that promoter hypermethylation and hemizygous deletion were found in a subset of gastric cancer tissues and cell lines and restoration of KLF4 expression induced typical apoptosis in gastric cancer cells. Finally, we observed an inverse correlation between decreased KLF4 expression and survival...

The MUC gene family, Their role in the diagnosis and prognosis of gastric cancer

Senapati, Shantibhusan; Sharma, Poonam; Bafna, Sangeeta; Roy, Hemant K.; Batra, Surinder K.
Fonte: Murcia : F. Hernández Publicador: Murcia : F. Hernández
Tipo: Artigo de Revista Científica Formato: application/pdf
ENG
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Early diagnosis of gastric cancer and its differential diagnosis from other non-malignant gastric diseases like gastritis is still a major clinical problem. Most patients are asymptomatic in the early stages of gastric cancer, and there is no reliable marker available for the early and specific diagnosis of gastric cancer. Many attempts have been made to define the biological profile of gastric cancer to improve the chances of its early diagnosis, prognosis and treatment. Several studies have shown the aberrant expression profile of mucins in different malignancies, suggesting that mucins have a great potential to be used as a diagnostic and prognostic marker in gastric cancer. In this review, we have briefly described the different types of gastric adenocarcinomas and the progression of gastric cancer. Furthermore, the role of mucins and their related carbohydrate epitope is discussed in the normal stomach and in the diagnosis and prognosis of gastric adenocarcinomas.

Instabilidade de microsatelites no cancer gástrico solitário e esporádico; Microsatellite instability in solitary and sporadic gastric cancer

Perez, Rodrigo Oliva; Jacob, Carlos Eduardo; D'Ottaviano, Fabricio L'ofreddo; Alvarenga, Conrado; Ribeiro, Adriana Safatle; Ribeiro Jr., Ulysses; Bresciani, Cláudio José Caldas; Zilberstein, Bruno; Krieger, José Eduardo; Habr-Gama, Angelita; Gama-Rodri
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; Formato: application/pdf
Publicado em 01/01/2004 ENG
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A presença de Instabilidade de microsatellites (IMS) tem sido relatada no cancer gastrico e associada a pacientes com idade mais avançada, localização mais distal do tumor, estadios mais precoces e melhor prognostico. Relatamos neste prospectivo estudo envolvendo 24 pacientes com cancer gastrico solitario e esporadico, a incidencia de IMS, sua correlação com parametros epidemiologicos, clinicos e anatomo patológicos e o seu impacto sobre a sobrevida geral e livre de doença. PACIENTES E MÉTODOS: Todos os pacientes haviam sido tratados com cirurgia radical. Fragmentos de tecido normal e tumoral eram extraidos das peças e armazenados a -80ºC antes da extração e purificação DNA. Realizava-se então a amplificação com PCR utilizando marcadores específicos de microsatelites. Os tumores que apresentavam produtos de amplificação anormais foram considerados positivos para IMS. RESULTADOS: Cinco pacientes (21%) apresentaram Instabilidade de microsatelites (IMS+) com pelo menos um marcador (primer) No grupo de pacientes com adenocarcinomas gástricos do tipo histológico de Lauren, três apresentavam IMS (23%) enquanto no grupo portador de cancar gástrico difuso, dois pacientes mostraram IMS (19%).. Embora haja uma tendência dos pacientes IMS+ apresentarem tumores de localização mais proximal...

P53 and Rb tumor suppressor gene alterations in gastric cancer; Alterações dos genes supressores tumorais p53 e Rb no câncer gástrico

Mattar, Rejane; Nonogaki, Suely; Silva, Cleonice; Alves, Venancio; Gama-Rodrigues, Joaquim J.
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; Formato: application/pdf
Publicado em 01/01/2004 ENG
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A inativação de genes supressores tumorais tem sido freqüentemente observada na carcinogênese gástrica. O nosso objetivo foi estudar o envolvimento dos genes p53, APC, DCC e Rb no câncer gástrico. MÉTODO: Vinte e dois casos de câncer gástrico foram estudados por PCR-LOH (reação de polimerase em cadeia- perda de alelo heterozigoto) dos genes p53, APC, DCC e Rb; e por PCR-SSCP (reação de polimerase em cadeia- polimorfismo de conformação de cadeia única) dos exons 5-6 e exons 7-8 do gene p53, empregando 35S-dATP e expressão de p53 por imunoperoxidase com monoclonal anti-p53. RESULTADOS E DISCUSSÃO: Perda de alelo heterozigoto não foi detectada nos genes estudados; deleção homozigótica foi observada no gene Rb em 23% (3/13) dos casos de câncer gástrico do tipo intestinal. Desvio de motilidade de banda nos exons 5-6 e/ou exons 7-8, indicando mutação do gene p53 foi encontrada em 18 casos (81.8%). A expressão de p53 foi positiva nas células de câncer gástrico em 14 casos (63.6%). A mucosa gástrica normal não corou com anti-p53, portanto, a reatividade imune deve representar formas mutantes. A correlação de desvio de motilidade de banda e expressão imune de p53 não foi significante (p=0.90). Não houve correlação entre as alterações genéticas e a extensão da doença. CONCLUSÃO: A inativação dos genes p53 e Rb tem papel na carcinogênese gástrica no nosso meio. A perda do gene Rb observada apenas no câncer gástrico do tipo intestinal deve ser avaliada posteriormente em associação com infecção pelo Helicobacter pylori. O gene p53 estava afetado em ambos os tipos histopatológicos.; Inactivation of tumor suppressor genes has been frequently observed in gastric carcinogenesis. Our purpose was to study the involvement of p53...

DNA mismatch repair gene methylation in gastric cancer in individuals from northern Brazil

Moura Lima,Eleonidas; Ferreira Leal,Mariana; de Arruda Cardoso Smith,Marília; Rodríguez Burbano,Rommel; Pimentel de Assumpção,Paulo; Bello,Maria Jose; Rey,Juan Antonio; Ferreira de Lima,Francinaldo; Casartelli,Cacilda
Fonte: Biocell Publicador: Biocell
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2008 EN
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Gastric cancer is one of the most common malignancies. DNA methylation is implicated in DNA mismatch repair genes deficiency. In the present study, we evaluated the methylation status of MLH1, MSH2, MSH6 and PMS2 in 20 diffuse- and 26 intestinal-type gastric cancer samples and 20 normal gastric mucosal of gastric cancer patients from Northern Brazil. We found that none of the nonneoplastic samples showed methylation of any gene promoter and 50% of gastric cancer samples showed at least one methylated gene promoter. Methylation frequencies of MLH1, MSH2, MSH6 and PMS2 promoter were 21.74%, 17.39%, 0% and 28.26% respectively in gastric cancer samples. MLH1 and PMS2 methylation were associated with neoplastic samples compared to nonneoplastic ones. PMS2 methylation was associated with diffuse-and intestinal-type cancer compared with normal controls. Intestinal-type cancer showed significant association with MLH1 methylation. Diffuse-type cancer was significantly associated with MSH2 methylation. Our findings show differential gene methylation in tumoral tissue, which allows us to conclude that methylation is associated with gastric carcinogenesis. Methylation of mismatch repair genes was associated with gastric carcinogenesis and may be a helpful tool for diagnosis...