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Association between Helicobacterpylori, Epstein-Barr virus, human papillomavirus and gastric adenocarcinomas

World Journal of Gastroenterology 2018年第43期24卷 4928-4938页

作者： Carolina Rosal Teixeira de Souza Marcelli Carolini Alves Almeida Andre Salim Khayat Emerson Lucena da Silva Paulo Cardoso Soares Luiz Claudio Chaves rommel Mario rodriguez burbano Laboratory of Human Cytogenetics Institute of Biological Sciences Federal University of Para Belem Para 66075-110 Brazil Oncology Research Center Federal University of Para Joao deBarros Barreto University Hospital Belem Para 66073-000Brazil Ophir Loyola Hospital Belem Para 66060-281 Brazil

AIM TO correlate Helicobacter pylori （H. pylorli）, EpsteinBarr virus （EBV） and human papillomavirus （HPV） with gastric cancer （GC） cases in Para State, *** Tissue samples were obtained from 302 gastric adenocarcinomas. A rapid urease test was used to detect the presence of H. pylori, and the presence of the cagA gene in the HP-positive samples was confirmed by PCR. An RNA in situ hybridization test designed to complement Eberl RNA was used to detect the presence of EBV in the samples, and the L1 region of HPV was detected using nested PCR. Positive HPV samples were genotyped and analyzed for E6 and E7 viral gene expression. Infections were also correlated with the clinical and pathological characteristics of the *** The majority of the 302 samples analyzed were obtained from men （65%） aged 55 years or older （67%） and were classified as the intestinal subtype （55%）. All three pathogens were found in the samples analyzed in the present study （H. pylori： 87%, EBV： 20%, HPV： 3%）. Overall, 78% of the H. pylori-positive （H. pylorl＋） samples were cagA＋（H. pylori-cagA＋）, and there was an association between the cytotoxic product of this gene and EBV. Coinfections of H. pylori-cagA＋ and EBV were correlated with the most advanced tumor stages. Although only 20% of the tumors were positive for EBV, infection with this virus was associated with distant metastasis. Only the HPV 16 and 18 strains were found in the samples, although no expression of the E6 and E7 oncoproteins was detected. The fundus of the stomach was the region least affected by the *** HPV was not involved in gastric tumorigenesis. Prophy- lactic and therapeutic measures against H. pylori and EBV may prevent the development of GC, especially the more aggressive forms.

关键词： Gastric cancer Gastric adenocarcinomas Microorganisms Helicobacter pylori cagA Epstein-Barr virus Human papillomavirus

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Identification of IL11RA and MELK amplification in gastric cancer by comprehensive genomic profiling of gastric cancer cell lines

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World Journal of Gastroenterology 2016年第43期22卷 9506-9514页

作者： Danielle Queiroz Calcagno Sylvia Santomi Takeno Carolina Oliveira Gigek Mariana Ferreira Leal Fernanda Wisnieski Elizabeth Suchi Chen Taíssa Maíra Thomaz Araújo Eleonidas Moura Lima Maria Isabel Melaragno Samia Demachki Paulo Pimentel Assumpcao rommel rodriguez burbano Marília Cardoso Smith Disciplina de Genética Departamento de Morfologia e GenéticaUniversidade Federal de Sao Paulo Núcleo de Pesquisas em Oncologia Hospital Universitário Joao de Barros Barreto Departamento de Biologia Molecular Universidade Federal da Paraíba Disciplina de Gastroenterologia Cirúrgica Universidade Federal de Sao Paulo Departamento de Ortopedia e Traumatologia Universidade Federal de Sao Paulo

AIM To identify common copy number alterations on gastric cancer cell *** Four gastric cancer cell lines(ACP02, ACP03, AGP01 and PG100) underwent chromosomal comparative genome hybridization and array comparative genome hybridization. We also confirmed the results by fluorescence in situ hybridization analysis using the bacterial artificial chromosome clone and quantitative real time PCR *** The amplification of 9p13.3 was detected in all cell lines by both methodologies. An increase in the copy number of 9p13.3 was also confirmed by fluorescence in situ hybridization analysis. Moreover, the interleukin 11 receptor alpha(IL11RA) and maternal embryonic leucine zipper kinase(MELK) genes, which are present in the 9p13.3 amplicon, revealed gains of the MELK gene in all the cell lines studied. Additionally, a gain in the copy number of IL11 RA and MELK was observed in 19.1%(13/68) and 55.9%(38/68) of primary gastric adenocarcinoma samples, respectively. CONCLUSION The characterization of a small gain region at 9p13.3 in gastric cancer cell lines and primary gastric adenocarcinoma samples has revealed MELK as a candidate target gene that is possibly related to the development of gastric cancer.

关键词： IL11RA Gastric cancer Genomic profiling MELK 9p13.3

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DNA and histone methylation in gastric carcinogenesis

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World Journal of Gastroenterology 2013年第8期19卷 1182-1192页

作者： Danielle Queiroz Calcagno Carolina Oliveira Gigek Elizabeth Suchi Chen rommel rodriguez burbano Marília de Arruda Cardoso Smith Department of Morphology and Genetics Federal University of Sao PauloSao PauloSP 04023-900Brazil Laboratory of Human Cytogenetics Institute of Biological SciencesFederal University of ParáBelémPA 66075-110Brazil

Epigenetic alterations contribute significantly to the development and progression of gastric cancer,one of the leading causes of cancer death *** refers to the number of modifications of the chromatin structure that affect gene expression without altering the primary sequence of DNA,and these changes lead to transcriptional activation or silencing of the *** the years,the study of epigenetic processes has increased,and novel therapeutic approaches that target DNA methylation and histone modifications have emerged.A greater understanding of epigenetics and the therapeutic potential of manipulating these processes is necessary for gastric cancer ***,we review recent research on the effects of aberrant DNA and histone methylation on the onset and progression of gastric tumors and the development of compounds that target enzymes that regulate the epigenome.

关键词： Epigenetic DNA methylation Histone methylation Gastric cancer Gastric carcinogenesis

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Presence of c.3956del C mutation in familial adenomatous polyposis patients from Brazil

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World Journal of Gastroenterology 2015年第31期21卷 9413-9419页

作者： Caroline Aquino Moreira-Nunes Diego di Felipe ávila Alcantara Sérgio Figueiredo Lima-Júnior Sandro Roberto de Araújo Cavalléro Juan Antonio Rey Giovanny Reboucas Pinto Paulo Pimentel de Assumpcao rommel rodriguez burbano Biological Science Institute Federal University of Pará Nucleus of Research in Oncology Federal University of Pará Molecular Neuro-oncogenetics Laboratory Research Unit-Unidad de InvestigaciónHospital Universitario La Paz Genetics and Molecular Biology Laboratory Federal University of Piaui

AIM: To characterize APC gene mutations and correlate them with patient phenotypes in individuals diagnosed with familial adenomatous polyposis(FAP) in northern Brazil. METHODS: A total of 15 individuals diagnosed with FAP from 5 different families from the north of Brazil were analyzed in this study. In addition to patients with histopathological diagnosis of FAP,family members who had not developed the disease were also tested in order to identify mutations and for possible genetic counseling. All analyzed patients or their guardians signed a consent form approved by the Research Ethics Committee of the Jo?o de Barros Barreto University Hospital(Belem,Brazil). DNA extracted from the peripheral blood of a member of each of the affected families was subjected to direct sequencing. The proband of each family was sequenced to identify germline mutations using the Ion Torrent platform. To validate the detected mutations,Sanger sequencing was also performed. The samples from all patients were also tested for the identification of mutations by real-time quantitative polymerase chain reaction using the amplification refractory mutation system. RESULTS: Through interviews with relatives and a search of medical records,it was possible to construct genograms for three of the five families included in the study. All 15 patients from the five families with FAP exhibited mutations in the APC gene,and all mutations were detected in exon 15 of the APC gene. In addition to the patients with a histological diagnosis of FAP,family members without disease symptoms showed the mutation in the APC gene. In the present study,we detected two of the three most frequent germline mutations in the literature: the mutation at codon 1309 and the mutation at codon 1061. The presence of c.3956 del C mutation was found in all families from this study,and suggests that this mutation was introduced in the population of the State of Pará through ancestor immigration(i.e.,a de novo mutation that arose

关键词： Familial adenomatous polyposis APC Torrent sequencing Colorectal cancer

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Traps and trumps from adjacent-to-tumor samples in gastric cancer research

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Chinese Journal of Cancer Research 2018年第5期30卷 564-567页

作者： Paulo Pimentel de Assumpcao Andre Salim Khayat Taissa Maira Thomaz Araujo Williams Fernandes Barra Geraldo Ishak Mine Maria Pereira Cruz Ramos Sidney Emanuel Batista dos Santos Andrea Kely Campos Ribeiro dos Santos Samia Demachki Paula Barauna de Assumpcao Danielle Queiroz Calcagno Ney Pereira Carneiro dos Santos Monica Barauna de Assumpcao Fabiano Cordeiro Moreira Andre Mauricio Ribeiro dos Santos Carolina Barauna de Assumpcao Gregory Joseph Riggins rommel Mario rodriguez burbano Oncology Research Center Federal University of Para Belem 66075-110 Brazil PhD Program in Genetics and Molecular Biology Federal University of Para Belem 66075-110 Brazil Gastrointestinal Endoscopy Service Joao de Barros Barreto University Hospital Belem 66073-000 Brazil Department of Surgical Oncology Oswaldo Cruz Germany Hospital Sao Paulo 01327-001 Brazil Department of Neurosurgery Johns Hopkins University Baltimore 21287 USA Laboratory of Molecular Biology Ophir Loyola Hospital Belem 66060-281 Brazil

The search for cancer biomarkers is frequently based on comparisons between tumors and adjacent-to-tumor samples. However, even after histological confirmation of been free of cancer cells, these adjacent-to-tumor samples might harbor molecular alterations which are not sufficient to cause them to look like cancer, but can differentiate these cells from normal cells. When comparing them, potential biomarkers are missed, and mainly the opportunity of finding initial aberrations presents in both tumors and adjacent samples, but not in true normal samples from non-cancer patients, resulting in misinterpretations about the carcinogenic process. Nevertheless, collecting adjacent-to-tumor samples brings trumps to be explored. The addition of samples from non-cancer patients opens an opportunity to increase the finds of the molecular cascade of events in the carcinogenic process. Differences between normal samples and adjacent samples might represent the first steps of the carcinogenic process. Adding samples of non-cancer patients to the analysis of molecular alterations relevant to the carcinogenic process opens a new window of opporttmides to the discovery of cancer biomarkers and molecular targets.

关键词： Adjacent-to-tumor trumps traps

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Role of mi RNAs and their potential to be useful as diagnostic and prognostic biomarkers in gastric cancer

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World Journal of Gastroenterology 2016年第35期22卷 7951-7962页

作者： Kelly Cristina da Silva Oliveira Taíssa Maíra Thomaz Araújo Camila Inagaki Albuquerque Gabriela Alcantara Barata Carolina Oliveira Gigek Mariana Ferreira Leal Fernanda Wisnieski Fernando Augusto Rodrigues Mello Junior André Salim Khayat Paulo Pimentel de Assumpcao rommel Mário rodriguez burbano Marília Cardoso Smith Danielle Queiroz Calcagno Núcleo de Pesquisas em Oncologia Universidade Federal do Pará Hospital Universitário Joao de Barros Barreto Disciplina de Genética Departamento de Morfologia e Genética Universidade Federal de Sao Paulo Laboratório de Citogenética Humana Instituto de Ciências Biológicas Universidade Federal do Pará

Alterations in epigenetic control of gene expression play an important role in many diseases, including gastric cancer. Many studies have identified a large number of upregulated oncogenic mi RNAs and downregulated tumour-suppressor mi RNAs in this type of cancer. In this review, we provide an overview of the role of mi RNAs, pointing to their potential to be useful as diagnostic and/or prognostic biomarkers in gastric cancer. Moreover, we discuss the influence of polymorphisms and epigenetic modifications on mi RNA activity.

关键词： Gastric cancer Epigenetic Diagnostic biomarkers miRNAs Prognostic biomarkers

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Advances in gastric cancer research will light the way to control this cancer

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Chinese Journal of Cancer Research 2022年第6期34卷 575-578页

作者： Paulo Pimentel de Assumpcao rommel Rodrigues burbano Universidade Federal do Para Nucleo de Pesquisas em OncologiaBelem-Para-Brasil 66075-110Brazil Hospital Ophir Loyola Laboratorio de Biologia MoleculaBelém-Para-Brasil 66063-240Brazil

Gastric adenocarcinoma(GC)is one of the most heterogeneous cancers,posing challenges to wide applications of the discoveries when compared to other ***,the benefits of research in the fight against GC are extraordinary,and even taking in mind the immense complexity of this disease,optimism is a great message to take *** advances in GC research will pave the way for GC effective control,helping to save lives,together with permitting sustainable real-life support for those needing complex and high-expense interventions.

关键词： Gastric cancer research innovations

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MYC and gastric adenocarcinoma carcinogenesis

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World Journal of Gastroenterology 2008年第39期14卷 5962-5968页

作者： Danielle Queiroz Calcagno Mariana Ferreira Leal Paulo Pimentel Assumpo Marília de Arruda Cardoso Smith rommel Rodríguez burbano Human Cytogenetics Laboratory Biology Science InstituteFederal University of ParáBelém PA 66075-900Brazil Genetics Division Department of Morphology and GeneticsFederal University of So PauloSo Paulo SP 04023-900Brazil Joo de Barros Barreto University Hospital Federal University of ParáBelém PA 66073-000Brazil

MYC is an oncogene involved in cell cycle regulation, cell growth arrest, cell adhesion, metabolism, ribosome biogenesis, protein synthesis, and mitochondrial function. It has been described as a key element of several carcinogenesis processes in humans. Many studies have shown an association between MYC deregulation and gastric cancer. MYC deregulation is also seen in gastric preneoplastic lesions and thus it may have a role in early gastric carcinogenesis. Several studies have suggested that amplification is the main mechanism of MYC deregulation in gastric cancer. In the present review, we focus on the deregulation of the MYC oncogene in gastric adenocarcinoma carcinogenesis, including its association with Helicobacterpylori （Hpylon] and clinical applications.

关键词： MYC Gastric adenocarcinoma Gastric preneoplastic lesions Gastric carcinogenesis Helicobacter pylori

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Clinical implication of 14-3-3 epsilon expression in gastric cancer

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World Journal of Gastroenterology 2012年第13期18卷 1531-1537页

作者： Mariana Ferreira Leal Danielle Queiroz Calcagno Smia Demachki Paulo Pimentel Assumpo Roger Chammas rommel Rodríguez burbano Marília de Arruda Cardoso Smith Genetics Division Department of Morphology and GeneticFederal University of So PauloSo Paulo 04023-900Brazil Pathology Service Joo de Barros Barreto University HospitalFederal University of ParáBelém 60673-000Brazil Surgery Service Joo de Barros Barreto University HospitalFederal University of ParáBelém 60673-000Brazil Laboratory of Experimental Oncology School of MedicineUniversity of So PauloSo Paulo 01246-903Brazil Human Cytogenetics Laboratory Institute of Biological SciencesFederal University of ParáBelém 66073-000Brazil

AIM:To evaluate for the first time the protein and mRNA expression of 14-3-3εin gastric ***:14-3-3εprotein expression was determined by western blotting,and mRNA expression was examined by real-time quantitative RT-PCR in gastric tumors and their matched non-neoplastic gastric tissue ***:Authors observed a significant reduction of 14-3-3εprotein expression in gastric cancer(GC)samples compared to their matched non-neoplastic *** levels of 14-3-3εwere also associated with diffuse-type GC and early-onset of this *** data suggest that reduced 14-3-3εmay have a role in gastric carcinogenesis ***:Our results reveal that the reduced 14-3-3εexpression in GC and investigation of 14-3-3ε interaction partners may help to elucidate the carcino-genesis process.

关键词： Gastric cancer 14-3-3 epsilon YWHAE Geneexpression Protein expression

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Promoter hypermethylation of CDH1, FHIT, MTAP and PLAGL1 in gastric adenocarcinoma in individuals from Northern Brazil

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World Journal of Gastroenterology 2007年第18期13卷 2568-2574页

作者： Mariana Ferreira Leal Eleonidas Moura Lima Patrícia Natália Oliveira Silva Paulo Pimentel Assumpo Danielle Queiroz Calcagno Spencer Luiz Marques Payo rommel Rodríguez burbano Marília de Arruda Cardoso Smith Genetics Division Department of Morphology Federal University of So Paulo So Paulo SP Brazil Department of Biology Campus Ministro Reis Velloso/Parnába Federal University of Piauí PI Brazil Joo de Barros Barreto University Hospital Federal University of Pará Belém PA Brazil Human Cytogenetics and Toxicological Genetics Laboratory Department of Biology Center of Biological Sciences Federal University of Pará Belém PA Brazil Genetics and Molecular Biology Hemocenter Faculty of Medicine of Marília Marília SP Brazil

AIM：To evaluate the methylation status of CDH1, FHIT, MTAP and PLAGL1 promoters and the association of these findings with clinico-pathological characteristics.METHODS： Methylation-specific PCR （MSP） assay was performed in 13 nonneoplastic gastric adenocarcinorna, 30 intestinal-type gastric adenocarcinorna and 35 diffuse-type gastric adenocarcinorna samples from individuals in Northern Brazil. Statistical analyses were performed using the chi-square or Fisher＇s exact test to assess associations between rnethylation status and clinico-pathological characteristics.RESULTS： Hypermethylation frequencies of CDH1, FHIT, MTAPand PLAGL1 promoter were 98.7%, 53.9%, 23.1% and 29.5%, respectively. Hyperrnethylation of three or four genes revealed a significant association with diffuse-type gastric cancer compared with nonneoplastic cancer. A higher hyperrnethylation frequency was significantly associated with H pylori infection in gastric cancers, especially with diffuse-type. Cancer samples without lymph node metastasis showed a higher FHIT hypermethylation frequency. MTAP hypermethylation was associated with H pylori in gastric cancer samples, as well as with diffuse-type compared with intestinal-type. In diffuse-type, MTAP hypermethylation was associated with female gender.CONCLUSION： Our findings show differential gene methylation in tumoral tissue, which allows us to conclude that hypermethylation is associated with gastric carcinogenesis. MTAP promoter hypermethylation can be characterized as a marker of diffuse-type gastric cancer, especially in women and may help in diagnosis, prognosis and therapies. The H pylori infectious agent was present in 44.9% of the samples. This infection may be correlated with the carcinogenic process through the gene promoter hypermethylation, especially the MTAP promoter in diffuse-type. A higher H pylori infection in diffuse-type may be due to greater genetic predisposition.

关键词： Gastric adenocarcinoma DNA hypermethylation CDH1 FHIT MTAP PLAGL1

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