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Master's Dissertation
DOI
https://doi.org/10.11606/D.5.2016.tde-11042016-110222
Document
Author
Full name
Evelise Pelegrinelli Zaidan
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2015
Supervisor
Committee
Ribeiro Júnior, Ulysses (President)
Sallum, Rubens Antonio Aissar
Forones, Nora Manoukian
Title in Portuguese
Análise de polimorfismos das enzimas ciclooxigenase-2 e metilenotetrahidrofolato redutase em pacientes com câncer de esôfago
Keywords in Portuguese
Adenocarcinoma
Carcinoma de células escamosas
Ciclo-oxigenase 2
Metilenotetra-hidrofolato redutase(NADPH2)
Neoplasias esofágicas
Polimorfismo de nucleotídeo único
Polimorfismo genético
Abstract in Portuguese
Introdução: O estudo de polimorfismos genéticos pode permitir maior conhecimento sobre os fatores de risco, progressão e susceptibilidade ao câncer do esôfago. A enzima ciclooxigenase-2 (COX-2) é induzida em resposta ao fator de crescimento e citocinas, sendo expressa nas doenças inflamatórias, lesões pré-malignas e tumores de esôfago. O produto do metabolismo do folato, pela enzima metilenotetrahidrofolato redutase (MTHFR), atua na síntese do DNA. A alteração ou a inibição da atividade desta enzima aumenta a suscetibilidade a mutações, danos e metilação aberrante do DNA, o que altera a expressão gênica de supressores de tumor e proto-oncogenes, potenciais fatores de risco para o câncer de esôfago. Objetivo: Investigar a frequência dos polimorfismos COX-2 (-1195A > G e 8473T > C) e MTHFR (677C > T e 1298C > A) em pacientes com câncer de esôfago, verificar as associações entre a frequência desses polimorfismos com a susceptibilidade à esta doença e aos fatores clínicos, epidemiológicos e patológicos. Metodologia: Inclui-se cento e nove pacientes com o diagnóstico de câncer de esôfago, submetidos à esofagectomia. Cento e dois indivíduos, pareados quanto ao sexo e idade, sem histórico individual ou familial de câncer, constituem o grupo controle. O DNA genômico foi isolado do creme leucocitário de sangue periférico e a genotipagem foi realizada através dos kits TaqMan ® SNP Genotyping Assays, seguida da amplificação pela reação em cadeia da polimerase e análise em tempo real (RT-PCR). Os resultados dos polimorfismos encontrados foram associados aos dados epidemiológicos e clinicopatológicos destes pacientes. Utilizou-se a regressão logística para avaliar as associações entre os polimorfismos e o risco de desenvolver o câncer de esôfago, com intervalos de confiança de 95%. Resultados: A presença do alelo COX-2+8437C (p=0,016) e dos haplótipos COX-21195A/COX2843C (p=0,002) e COX-21195G/COX28437T (p=0,01) indicaram associação com a doença. Os indivíduos com câncer do esôfago portadores do polimorfismo MTHFR 677TT apresentaram maior risco de óbito pela doença (p = 0,045). Conclusão: A presença do alelo COX-2+8437C e dos haplótipos COX21195A/COX2843C e COX-21195G/COX28437T associaram-se ao câncer de esôfago. O genótipo homozigoto polimórfico MTHFR677TT está relacionado ao pior prognóstico em pacientes com câncer de esôfago
Title in English
Analysis of the cyclooxygenase-2 and methylenetetrahydrofolate reductase genes polymorphisms in esophageal cancer
Keywords in English
Adenocarcinoma
Carcinoma squamous cell
Cyclooxigenase 2
Esophageal neoplasms
Methylenetetrahydrofolate reductase (NADPH2)
Polymorphism genetic
Polymorphism single nucleotide
Abstract in English
Introduction: The study of genetic polymorphisms may allow better understanding of the risk factors, progression and susceptibility to cancer of the esophagus. The cyclooxygenase-2 enzyme (COX-2) is induced in response to growth factors and cytokines and is expressed in inflammatory diseases, premalignant and esophageal tumors. The product of folate metabolism, the enzyme methylenetetrahydrofolate reductase (MTHFR), engaged in DNA synthesis. Changing or inhibiting the activity of this enzyme increases the susceptibility to mutations, damage and aberrant DNA methylation, which alters gene expression of tumor suppressors and proto-oncogenes, potential risk factors for esophageal cancer. Objective: To investigate the frequency of COX-2 (-1195A > G and 8473T > C) and MTHFR (677C > T and 1298C > A) polymorphisms in patients with esophageal cancer, verify the associations between the frequency of these polymorphisms with susceptibility to this disease and clinical, epidemiological and pathological factors. Methodology: This study includes up one hundred nine patients diagnosed with esophageal cancer who underwent esophagectomy. One hundred and two individuals, matched for sex and age, no individual or familial history of cancer, constitute the control group. Genomic DNA was isolated from the peripheral blood buffy coat and genotyping was performed using the TaqMan ® SNP Genotyping Assays kits, followed by amplification by polymerase chain reaction and real-time analysis (RT-PCR). The results of found polymorphisms were associated with epidemiological and clinicopathological these patients. Logistic regression was used to assess associations between polymorphisms and the risk of developing esophageal cancer, with 95% confidence intervals. Results: The presence of COX-2 + 8437C allele (p = 0.016) and haplotypes COX-21195A / COX2843C (p = 0.002) and COX-21195G / COX28437T (p = 0.01) indicated association with the disease. Individuals with esophageal cancer carrying the MTHFR 677TT polymorphism had higher risk of death from the disease (p = 0.045). Conclusion: The presence of COX-2+8437C allele and haplotype COX21195A/ COX2843C and COX-21195G/COX28437T was associated with esophageal cancer. The polymorphic homozygous genotype MTHFR677TT is related to worse prognosis in patients with esophageal cancer
 
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Publishing Date
2016-04-11
 
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