Associação entre polimorfismos em genes envolvidos no metabolismo do metotrexato e a ocorrência de mucosite oral em pacientes pediátricos com leucemia

Abstract

Chemoinduced oral mucositis is an inflammatory mucosal response to chemotherapeutic action. Polymorphisms in the genes involved in methotrexate metabolism (MTX) have been caused as evidence associated with the occurrence of oral mucositis. The aim of this dissertation was to investigate a relationship of genetic polymorphisms in the development of oral mucositis in children and adolescents who used chemotherapy using MTX. For this, a systematic review with meta-analysis and a longitudinal survey were performed. For review, bibliographic searches were performed in the databases: PubMed, Scopus, Lilacs, Cochrane, Web of Science and Open Gray, until May 2019. Observational studies with children and / or adolescents with MTX chemotherapy, with some polymorphism and who described an oral mucositis as unfocused were selected using the CEEC strategy. Studies containing the number of individuals with and without genetic polymorphisms, with and without oral mucositis, and who performed statistical statistics associated with selected items. Prohibit methodological quality by the instrument of Fowkes and Fulton (1991). Two meta-analyzes were conducted in Review Manager v. 5.2 (with all polymorphisms found and with polymorphisms that were repeated in more than one study). The quality of the evidence was assessed by GRADE. For the longitudinal study, 64 patients were evaluated by the modified oral assessment guide (OAG) for diagnosis of oral mucositis. The biological material used was saliva, where oral epithelial cells were extracted from DNA. Polymorphisms: MTHFR C677T (rs1801133), DNMT3B C-149T (rs2424913), ABCC2 C-24T (rs717620), ABCG2 G34A (rs2231137) and ABCG2 C421A (rs2231137) and were analyzed by PCR-RFLP polymorphism and length the results observed on 6% polyacrylamide gel stained with silver nitrate or GelRed®. Demographic and hematological data were collected from medical records. Descriptive and inferential statistics were performed using the chi-square, Fisher's exact test and Man-Whitney U test (p≤0.05). The search for systematic review resulted in 61 articles, 9 of which were eligible. A total sample was 1775 individuals, aged 1 to 19 years, with leukemia or lymphoma. Twenty-nine polymorphisms studied and their associations with oral mucositis were investigated, being MTHFR C677T or more investigated. Seven studies published in the sample selection. No association was observed between polymorphisms and occurrence of oral mucositis, either meta-analysis with all polymorphisms (RR = 1.14; I² = 18%; p = 0.22) or performed with the polymorphisms that were repeated in the studies (RR = 0.96; I² = 20%; p = 0.29), with very low level of scientific evidence. In the longitudinal study, there was a predominance of males (56.2%) and average age of 10.8 years (± 4.9). Among the patients with oral mucositis, 65.3% were severely affected (MOG). There was an association between C421A polymorphism (rs2231142) and oral mucositis (RR = 8.33; CI = 0.09 - 0.47; p = 0.02;), as well as between MOG and leukocyte count (p = 0 .03) and MOG and age (p = 0.02). The systematic review concluded that oral mucositis and genetic polymorphisms are not associated; however, the risk of disease and the poor quality of scientific research suggest further studies with greater methodological rigor, or what drives longitudinal studies. In this study, we concluded that the presence of C421A ABCG2 polymorphism (rs2231142) increases the likelihood of oral mucositis. Younger children and adolescents with fewer leukocytes are more likely to develop an oral mucositis severe.