Farmacogenética do Gene TPMT na resposta A 6-Mercaptopurina, em pacientes com Leucemia Linfoblástica Aguda
Acute Lymphoblastic Leukemia (ALL) is the most common type of cancer in children under 15 years of age. 6-mercaptopurine (6-MP) is one of the most widely used chemotherapeutic agents in the treatment of childhood ALL. Polymorphisms in thiopurine S-methyltransferase gene (TPMT) may be associated with...
| Autor principal: | LIMA, Carlos Henrique Vasconcelos de |
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| Grau: | Dissertação |
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Universidade Federal do Pará
2017
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http://repositorio.ufpa.br/jspui/handle/2011/7252 |
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ir-2011-72522017-12-20T13:41:50Z Farmacogenética do Gene TPMT na resposta A 6-Mercaptopurina, em pacientes com Leucemia Linfoblástica Aguda LIMA, Carlos Henrique Vasconcelos de SANTOS, Ney Pereira Carneiro dos http://lattes.cnpq.br/1290427033107137 ASSUMPÇÃO, Paulo Pimentel de http://lattes.cnpq.br/7323606327039876 Farmacogenética Polimorfismo genético Neoplasias Toxicidade Câncer em crianças Leucemia CNPQ::CIENCIAS DA SAUDE::MEDICINA::CLINICA MEDICA::CANCEROLOGIA Acute Lymphoblastic Leukemia (ALL) is the most common type of cancer in children under 15 years of age. 6-mercaptopurine (6-MP) is one of the most widely used chemotherapeutic agents in the treatment of childhood ALL. Polymorphisms in thiopurine S-methyltransferase gene (TPMT) may be associated with individual variation in the response to treatment of childhood ALL, such as increased severe toxicity (grade 3 and 4). The aim of this study was to associate polymorphisms of TPMT gene: TPMT*2 (238G>C), TPMT*3A (460G>A and 719A>G), TPMT*3B (460G>A), TPMT*3C (719A>G), TPMT* 8 (644G>A) and intronic variant rs12201199 (94T>A) with the occurrence of serious toxicities in patients with ALL treated with 6-MP, in Northern Brazil. One hundred thirty-seven pediatric patients with ALL and treated at the Ophir Loyola Hospital in the state of Pará were investigated. The rs12201199 polymorphism was genotyped by real-time PCR (equipment 7500 Real-Time PCR System) and other polymorphisms were genotyped by direct sequencing using the automated sequencer ABI PRISM 3130 Genetic Analyzer (Applied Biosytems, CA, USA). The haplotypes among the studied polymorphisms were derived via maximum likelihood estimates using the program PHASE. A panel of 48 markers Ancestry Informative was used as genomic control in the sample and statistical analyses were performed using SPSS v.20.0 software (SPSS, Chicago, IL, USA). All statistical tests considered the probability (p) significant when ≤0, 05. In relation to the genomic ancestry, it was noted that the ethnic composition of ALL patients was 44% Caucasian, 22% African and 34% Amerindian. Among the reported toxicities, infectious was most prevalent (86%), followed by hematological (65%), gastrointestinal (64.8%) and central nervous system toxicity (29.9%). Allele frequency of polymorphism rs12201199 was 0.482 among the studied subjects. The most prevalent haplotype variants were TPMT*3A (7.6%), followed by TPMT*3C and TPMT*8, both 7.3%. There was no significant association between poor metabolism profiles of TPMT with none of the serious toxicities reported in the studied patients with LLA. However, our data show that there is a significant relationship between the polymorphism of TPMT gene (rs12201199) and the occurrence of severe infectious toxicity during treatment of childhood ALL. It has been observed that patients who have mutant homozygous AA genotype for this polymorphism in TPMT gene have 4.098 times higher risk of presenting severe infectious toxicity during the treatment for childhood ALL compared to those with the other genotypes. This result may be important to help predict risk of toxicity during treatment, contributing to a better individual prognosis of patients with childhood ALL. Leucemia Linfoblástica Aguda (LLA) é o tipo de câncer mais frequente em crianças menores de 15 anos de idade. O 6-mercaptopurina (6-MP) é um dos agentes quimioterápicos mais amplamente utilizado no tratamento da LLA infantil. Polimorfismos no gene Tiopurina s-metiltransferase (TPMT) podem estar associados a variações individuais na resposta ao tratamento da LLA infantil, como aumento de toxicidade grave (grau 3 e 4). O objetivo deste trabalho foi associar polimorfismos do gene TPMT: TPMT*2 (238G>C), TPMT*3A (460G>A e 719A>G), TPMT*3B (460G>A), TPMT*3C (719A>G), TPMT*8 (644G>A) e a variante intrônica rs12201199 (94T>A) com a ocorrência de toxicidades graves em pacientes com LLA tratados com 6-MP, na Região Norte do Brasil. Foram investigados 137 pacientes infantis com LLA tratados no Hospital Ophir Loyola, no estado do Pará. O polimorfismo rs12201199 foi genotipado pela técnica de PCR em tempo Real (equipamento 7500 Real-Time PCR System) e os demais polimorfismos foram genotipados por sequenciamento direto, utilizando o sequenciador automático ABI PRISM 3130 Genetic Analyzer (Applied Biosytems, CA, USA). Os haplótipos entre os polimorfismos investigados foram derivados através de estimativas de máxima verossimilhança utilizando o programa PHASE. Foi empregado um painel de 48 Marcadores Informativos de Ancestralidade, como controle genômico na amostra e as análises estatísticas foram realizadas no programa SPSS v.20.0 (SPSS, Chicago, IL, EUA). Todos os testes estatísticos consideraram a probabilidade (p-valor) significativa quando ≤0,05. Em relação à ascendência genômica, observou-se que a composição étnica dos pacientes com LLA foi de 44% Europeu, 22% Africano e 34% Ameríndio. Entre as toxicidades relatadas, a infecciosa foi a mais prevalente (86%), seguida da hematológica (65%), da gastrointestinal (64,8%) e toxicidade no sistema nervoso central (29,9%). A frequência alélica do polimorfismo rs12201199 foi de 0,482 entre os indivíduos estudados. As variantes haplotípicas mais prevalentes foram TPMT*3A (7,6%), seguido pelo TPMT*3C e TPMT*8, ambos com 7,3%. Não foi observada uma associação significativa entre o perfil de metabolização deficiente da TPMT com nenhuma das toxicidades graves relatadas nos pacientes com LLA estudados. No entanto, os dados encontrados mostram que há uma significativa relação entre o polimorfismo do gene TPMT (rs12201199) e a ocorrência de toxicidade infecciosa grave durante o tratamento da LLA infantil. Foi observado que os pacientes que possuem o genótipo homozigoto mutante AA para o polimorfismo no gene TPMT têm um risco de 4,098 vezes maior de apresentar toxicidade grave infecciosa durante o tratamento para LLA infantil em relação aos que apresentam os outros genótipos. Este resultado pode ser importante para ajudar a predizer riscos de toxicidade durante o tratamento, contribuindo para um melhor prognóstico individual dos pacientes com LLA infantil. 2017-01-09T17:41:43Z 2017-01-09T17:41:43Z 2016-03-03 Dissertação LIMA, Carlos Henrique Vasconcelos de. Farmacogenética do Gene TPMT na resposta A 6-Mercaptopurina, em pacientes com Leucemia Linfoblástica Aguda. 2016. 107 f. Dissertação (Mestrado) - Universidade Federal do Pará, Núcleo de Pesquisas em Oncologia, Belém, 2016. Programa de Pós-Graduação em Oncologia e Ciências Médicas. http://repositorio.ufpa.br/jspui/handle/2011/7252 por Acesso Aberto application/pdf Universidade Federal do Pará Brasil Núcleo de Pesquisas em Oncologia UFPA Programa de Pós-Graduação em Oncologia e Ciências Médicas |
| institution |
Repositório Institucional - Universidade Federal do Pará |
| collection |
RI-UFPA |
| language |
por |
| topic |
Farmacogenética Polimorfismo genético Neoplasias Toxicidade Câncer em crianças Leucemia CNPQ::CIENCIAS DA SAUDE::MEDICINA::CLINICA MEDICA::CANCEROLOGIA |
| spellingShingle |
Farmacogenética Polimorfismo genético Neoplasias Toxicidade Câncer em crianças Leucemia CNPQ::CIENCIAS DA SAUDE::MEDICINA::CLINICA MEDICA::CANCEROLOGIA LIMA, Carlos Henrique Vasconcelos de Farmacogenética do Gene TPMT na resposta A 6-Mercaptopurina, em pacientes com Leucemia Linfoblástica Aguda |
| topic_facet |
Farmacogenética Polimorfismo genético Neoplasias Toxicidade Câncer em crianças Leucemia CNPQ::CIENCIAS DA SAUDE::MEDICINA::CLINICA MEDICA::CANCEROLOGIA |
| description |
Acute Lymphoblastic Leukemia (ALL) is the most common type of cancer in children under 15 years of age. 6-mercaptopurine (6-MP) is one of the most widely used chemotherapeutic agents in the treatment of childhood ALL. Polymorphisms in thiopurine S-methyltransferase gene (TPMT) may be associated with individual variation in the response to treatment of childhood ALL, such as increased severe toxicity (grade 3 and 4). The aim of this study was to associate polymorphisms of TPMT gene: TPMT*2 (238G>C), TPMT*3A (460G>A and 719A>G), TPMT*3B (460G>A), TPMT*3C (719A>G), TPMT* 8 (644G>A) and intronic variant rs12201199 (94T>A) with the occurrence of serious toxicities in patients with ALL treated with 6-MP, in Northern Brazil. One hundred thirty-seven pediatric patients with ALL and treated at the Ophir Loyola Hospital in the state of Pará were investigated. The rs12201199 polymorphism was genotyped by real-time PCR (equipment 7500 Real-Time PCR System) and other polymorphisms were genotyped by direct sequencing using the automated sequencer ABI PRISM 3130 Genetic Analyzer (Applied Biosytems, CA, USA). The haplotypes among the studied polymorphisms were derived via maximum likelihood estimates using the program PHASE. A panel of 48 markers Ancestry Informative was used as genomic control in the sample and statistical analyses were performed using SPSS v.20.0 software (SPSS, Chicago, IL, USA). All statistical tests considered the probability (p) significant when ≤0, 05. In relation to the genomic ancestry, it was noted that the ethnic composition of ALL patients was 44% Caucasian, 22% African and 34% Amerindian. Among the reported toxicities, infectious was most prevalent (86%), followed by hematological (65%), gastrointestinal (64.8%) and central nervous system toxicity (29.9%). Allele frequency of polymorphism rs12201199 was 0.482 among the studied subjects. The most prevalent haplotype variants were TPMT*3A (7.6%), followed by TPMT*3C and TPMT*8, both 7.3%. There was no significant association between poor metabolism profiles of TPMT with none of the serious toxicities reported in the studied patients with LLA. However, our data show that there is a significant relationship between the polymorphism of TPMT gene (rs12201199) and the occurrence of severe infectious toxicity during treatment of childhood ALL. It has been observed that patients who have mutant homozygous AA genotype for this polymorphism in TPMT gene have 4.098 times higher risk of presenting severe infectious toxicity during the treatment for childhood ALL compared to those with the other genotypes. This result may be important to help predict risk of toxicity during treatment, contributing to a better individual prognosis of patients with childhood ALL. |
| author_additional |
SANTOS, Ney Pereira Carneiro dos |
| author_additionalStr |
SANTOS, Ney Pereira Carneiro dos |
| format |
Dissertação |
| author |
LIMA, Carlos Henrique Vasconcelos de |
| title |
Farmacogenética do Gene TPMT na resposta A 6-Mercaptopurina, em pacientes com Leucemia Linfoblástica Aguda |
| title_short |
Farmacogenética do Gene TPMT na resposta A 6-Mercaptopurina, em pacientes com Leucemia Linfoblástica Aguda |
| title_full |
Farmacogenética do Gene TPMT na resposta A 6-Mercaptopurina, em pacientes com Leucemia Linfoblástica Aguda |
| title_fullStr |
Farmacogenética do Gene TPMT na resposta A 6-Mercaptopurina, em pacientes com Leucemia Linfoblástica Aguda |
| title_full_unstemmed |
Farmacogenética do Gene TPMT na resposta A 6-Mercaptopurina, em pacientes com Leucemia Linfoblástica Aguda |
| title_sort |
farmacogenética do gene tpmt na resposta a 6-mercaptopurina, em pacientes com leucemia linfoblástica aguda |
| publisher |
Universidade Federal do Pará |
| publishDate |
2017 |
| url |
http://repositorio.ufpa.br/jspui/handle/2011/7252 |
| _version_ |
1787148521860759552 |
| score |
11.653393 |