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Analysis of 12 variants in the development of gastric and colorectal cancers

World Journal of Gastroenterology 2017年第48期23卷 8533-8543页

作者： Giovanna C Cavalcante Marcos AT Amador Andre M Ribeiro dos santos Darlen C Carvalho Roberta B Andrade Esdras EB Pereira Marianne R Fernandes Danielle F Costa Ney PC santos Paulo P Assumpcao Andrea Ribeiro dos santos sidney santos Laboratório de Genética Humana e Médica Universidade Federal do Pará Núcleo de Pesquisas em Oncologia Universidade Federal do Pará

AIM To evaluate the relation between 12 polymorphisms and the development of gastric cancer(GC) and colorectal cancer(CRC).METHODS In this study,we included 125 individuals with GC diagnosis,66 individuals with CRC diagnosis and 475 cancer-free individuals. All participants resided in the North region of Brazil and authorized the use of their samples. The 12 polymorphisms(in CASP8,CYP2 E1,CYP19 A1,IL1 A,IL4,MDM2,NFKB1,PAR1,TP53,TYMS,UGT1 A1 and XRCC1 genes) were genotyped in a single PCR for each individual,followed by fragment analysis. To avoid misinterpretation due to population substructure,we applied a previously developed set of 61 ancestryinformative markers that can also be genotyped by multiplex PCR. The statistical analyses were performed in Structure v.2.3.4,R environment and SPSS v.20.RESULTS After statistical analyses with the control of confounding factors,such as genetic ancestry,three markers(rs79071878 in IL4,rs3730485 in MDM2 and rs28362491 in NFKB1) were positively associated with the development of GC. One of these markers(rs28362491) and the marker in the UGT1 A1 gene(rs8175347) were positively associated with the development of CRC. Therefore,we investigated whether the joint presence of the deleterious alleles of each marker could affect the development of cancer and we obtained positive results in all analyses. Carriers of the combination of alleles RP1 + DEL(rs79071878 and rs28361491,respectively) are at 10-times greater risk of developing GC than carriers of other combinations. Similarly,carriers of the combination of DEL + RARE(rs283628 and rs8175347) are at about 12-times greater risk of developing CRC than carriers of other combinations.CONCLUSION These findings are important for the comprehension of gastric and CRC development,particularly in highly admixed populations,such as the Brazilian population.

关键词： Inflammatory processes Immune response Genomic and cellular stability Gastric cancer Colorectal cancer Amazon

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Hereditary gastric cancer:Three rules to reduce missed diagnoses

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World Journal of Gastroenterology 2020年第13期26卷 1382-1393页

作者： Paula Assumpcao Taíssa Araújo André Khayat Geraldo Ishak sidney santos Williams Barra Joao Felipe Acioli Benedito Rossi Paulo Assumpcao Programa de Pós-Graduacao em Genética e Biologia Molecular Universidade Federal do ParáBelém 66075-110Brazil Núcleo de Pesquisas em Oncologia Universidade Federal do ParáBelém 66073-000Brazil Hospital Universitário Joao de Barros Barreto Universidade Federal do ParáBelém 66073-000Brazil Centro de Oncologia e Aconselhamento Genético Hospital Sírio LibanêsSao Paulo 01308-050Brazil

Gastric cancer remains one of the most lethal cancers.The incidence and mortality rates are quite similar.The main reason for the high mortality is diagnosis at advanced stages of disease,when treatment options are poor.One of the supposed strategies to overcome late-stage diagnosis is identifying people at high risk with the aim of establishing rigorous clinical control,including routine endoscopy and biopsies.Hereditary gastric cancer(HGC)syndromes,though representing a sizeable group to monitor for prevention or,at least,for early diagnosis,are apparently extremely rare.The low rate of HGC diagnosis might be related to the low rates of suspicion,insufficient familiarity about clinical diagnosis criteria,and the supposed conditional necessity of a molecular diagnosis.In this review,we will discuss simple measures to increase HGC diagnosis by applying three rules that might provide an opportunity for precision care to benefit the families affected by this disease.

关键词： Hereditary gastric cancer Rules Diagnosis

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Association of insertion-deletions polymorphisms with colorectal cancer risk and clinical features

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World Journal of Gastroenterology 2017年第37期23卷 6854-6867页

作者： Diego Marques Layse Raynara Ferreira-Costa Lorenna Larissa Ferreira-Costa Romualdo da Silva Correa Aline Maciel Pinheiro Borges Fernanda Ribeiro Ito Carlos Cesar de Oliveira Ramos Raul Hernandes Bortolin André Ducati Luchessi Andrea Ribeiro-dos-santos sidney santos Vivian Nogueira Silbiger Laboratório de Bioanálise e Biotecnologia Molecular Universidade Federal do Rio Grande do Norte Programa de Pós-graduacao em Ciências Farmacêutica Universidade Federal do Rio Grande do Norte Laboratório de Genética Humana e Médica Universidade Federal do Pará Departamento de Cirurgia Oncológica Liga Norte Riograndense Contra o Cancer Laboratório de Patologia eCitopatologia Liga Norte Riograndense Contra o Cancer Depart-amento de Análises Clínicas e Toxicológicas Universidade Federal do Rio Grande do Norte Núcleo de Pesquisas em Oncologia Universidade Federal do Pará

AIM To investigate the association between 16 insertiondeletions(INDEL) polymorphisms, colorectal cancer(CRC) risk and clinical features in an admixed population.METHODS O n e h u n d re d a n d fo r ty p a t i e n t s w i t h C R C a n d 140 cancer-free subjects were examined. Genomic DNA was extracted from peripheral blood samples. Polymorphisms and genomic ancestry distribution were assayed by Multiplex-PCR reaction, separated by capillary electrophoresis on the ABI 3130 Genetic Analyzer instrument and analyzed on Gene Mapper ID v3.2. Clinicopathological data were obtained by consulting the patients' clinical charts, intra-operative documentation, and pathology scoring.RESULTS Logistic regression analysis showed that polymorphism variations in IL4 gene was associated with increased CRC risk, while TYMS and UCP2 genes were associated with decreased risk. Reference to anatomical localization of tumor Del allele of NFKB1 and CASP8 were associated with more colon related incidents than rectosigmoid. In relation to the INDEL association with tumor node metastasis(TNM) stage risk, the Ins alleles of ACE, HLAG and TP53(6 bp INDEL) were associated with higher TNM stage. Furthermore, regarding INDEL association with relapse risk, the Ins alleles of ACE, HLAG, and UGT1A1 were associated with early relapse risk, as well as the Del allele of TYMS. Regarding INDEL association with death risk before 10 years, the Ins allele of SGSM3 and UGT1A1 were associated with death risk.CONCLUSION The INDEL variations in ACE, UCP2, TYMS, IL4, NFKB1, CASP8, TP53, HLAG, UGT1A1, and SGSM3 were associated with CRC risk and clinical features in an admixed population. These data suggest that this cancer panel might be useful as a complementary tool for better clinical management, and more studies need to be conducted to confirm these findings.

关键词： Colorectal cancer Ins-del polymorphism Admixed population Potential biomarker Diagnostic Risk stratification Prognostic Clinical features

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Piwi like RNA-mediated gene silencing 1 gene as a possible major player in gastric cancer

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World Journal of Gastroenterology 2018年第47期24卷 5338-5350页

作者： Taíssa Araújo Andre Khayat Luciana Quintana Danielle Calcagno Ronald Mourao Antonio Modesto Juliana Paiva Adhara Lima Fabiano Moreira Edivaldo Oliveira Michel Souza Moneeb Othman Thomas Liehr Eliana Abdelhay Renata Gomes sidney santos Paulo Assumpcao Núcleo de Pesquisas em Oncologia Universidade Federal do ParáBelém 66073-000Brazil Laboratório de Cultura de Tecidos e Citogenética Instituto Evandro ChagasBelém 66087-082Brazil Institute of Human Genetics Universitatsklinikum JenaJena 07747Germany Laboratório de Célula Tronco Centro de Transplante de Medula OsseaInstituto Nacional de Cancer Jose Alencar Gomes da SilvaRio de Janeiro 20230-130Brazil

AIM To establish a permanent piwi like RNA-mediated genesilencing 1(PIWIL1) gene knockout in AGP01 gastric cancer cell line using CRISPR-Cas9 system and analyze phenotypic modifications as well as gene expression alterations.METHODS CRISPR-Cas9 system used was purchased from Dharmacon GE Life Sciences(Lafayette, CO, United States) and permanent knockout was performed according to manufacturer's recommendations. Woundhealing assay was performed to investigate the effect of PIWIL1 knockout on migration capability of cells and Boyden chamber invasion assay was performed to investigate the effect on invasion capability. For the gene expression analysis, a one-color microarray-based gene expression analysis kit(Agilent Technologies, Santa Clara, CA, United States) was used according to the protocol provided by the manufacturer. RESULTS PIWIL1 gene knockout caused a significant decrease in AGP01 migration capacity as well as a significant decrease in cell invasiveness. Moreover, functional analysis based on grouping of all differentially expressed m RNAs identified a total of 35 genes(5 up-regulated and 30 down-regulated) encoding proteins involved in cellular invasion and migration. According to current literature, 9 of these 35 genes(DOCK2, ZNF503, PDE4 D, ABL1, ABL2, LPAR1, SMAD2, WASF3 and DACH1) are possibly related to the mechanisms used by PIWIL1 to promote carcinogenic effects related to migration and invasion, since their functions are consistent with the changes observed(being up-or down-regulated after knockout). CONCLUSION Taken together, these data reinforce the idea that PIWIL1 plays a crucial role in the signaling pathway of gastric cancer, regulating several genes involved in migration and invasion processes; therefore, its use as a therapeutic target may generate promising results in the treatment of gastric cancer.

关键词： Gastric cancer Piwi like RNA-mediated gene silencing 1 CRISPR-Cas9 Migration Invasion

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Interleukin-1 and TNF-α polymorphisms and Helicobacter pylori in a Brazilian Amazon population

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World Journal of Gastroenterology 2009年第12期15卷 1465-1471页

作者： Hivana Patricia Melo Barbosa Luisa Caricio Martins sidney Emanuel Batista dos santos Samia Demachki Mnica Baraúna Assumpo Charliana Damasceno Arago Tereza Cristina de Oliveira Corvelo Laboratory of Immunogenetics Federal University of Pará66075-110BelémBrazil Nucleus of Tropical Medicine Federal University of Pará66055-240BelémBrazil Laboratory of Human and Medical Genetics Federal University of Pará66075-110BelémBrazil Department of Pathology Joo de Barros Barreto Universitary HospitalFederal University of Pará66073-000BelémBrazil Department of Endoscopy Joo de Barros Barreto Universitary HospitalFederal University of Pará66073-000BelémBrazil

AIM:To study the association between Interleukin-1(IL-1)and tumor necrosis factor(TNF)-αpolymorphisms,infection by Helicobacter pylori(H pylori)and the development of gastrointestinal diseases.METHODS:Genomic DNA was extracted from the peripheral blood of 177 patients with various gastrointestinal diseases and from 100 healthy volunteers.The polymorphisms in IL-1βand TNF-αgenes were analyzed using the polymerase chain reactionrestriction fragment length polymorphism method(PCRRFLP)and those from IL-1RN with PCR.The presence of infection due to H pylori and the presence of the CagA toxin were detected by serology.The histopathological parameters in the gastric biopsies of the patients were according to the Sydney classification.RESULTS:A comparison of the frequencies of the different polymorphisms studied among the patients and the control group demonstrated that the allele IL1RN*2 was more frequent among patients with gastric ulcers and adenocarcinoma.Carriers of the allele ILRN*2 and those with reactive serology for anti-CagA IgG had a greater risk of developing peptic ulcer and gastric adenocarcinoma,as well as a higher degree of inflammation and neutrophilic activity in the gastric mucosa.CONCLUSION:Our results indicate a positive association between IL-1RN gene polymorphism and infection by positive H pylori CagA strains and the development of gastric ulcers and adenocarcinoma.

关键词：白细胞介素1 多态性分析法肿瘤坏死因子幽门螺杆菌 PCRRFLP 幽门螺旋杆菌组织病理学参数 RN基因多态性

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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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