RESUMO
The correlation of gene polymorphisms rs4025935 (large deletion), rs1695 (313A>G), rs71748309 (large deletion), and rs1800566 (609C>T) of GSTM1, GSTT1, and NQO1 genes encoding glutathione-S-transferases (GST) M1, P1, and T1 and NADPH-quinone oxidoreductase with the risk of development of classical Ph-negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, and primary myelofibrosis) was studied in the Caucasian ethnicity population of Vyatka region of the Russian Federation. It was found that NQO1*609T allele, NQO1*609T genotypes, and homozygous carriage of a deletion (null) allele of GSTT1 gene are associated with the risk of development of myeloproliferative neoplasms (OR=1.29, 95%CI=1.02-1.64, p=0.04; OR=1.39, 95%CI=1.04-1.85, p=0.03; and OR=1.48, 95%CI=1.03-2.12, p=0.03, respectively). However, no influence of GSTM1 and GSTP1 gene polymorphisms on the risk of development of myeloproliferative disorders was registered.
Assuntos
Glutationa Transferase/genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , Polimorfismo Genético , Xenobióticos/farmacocinética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biotransformação/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Deleção de Genes , Glutationa S-Transferase pi/genética , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Cromossomo Filadélfia , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
We studied the relationship between polymorphisms rs1800629 (-308G>A), rs28362491 (-94ins>del), and rs3834129 (-652ins>del) in the promoter regions of TNFA, NFKB1, and CASP8 genes, respectively, encoding TNF-α, nuclear transcription factor κB1 (NF-κB1), and caspase 8 (CASP8), and the risk and stages of chronic lymphocytic leukemia in ethnic Russians, residents of the Vyatka region of Russia. Allele -308A, genotype -308AA, and -308A genotypes (-308AA/-308AG) were associated with the risk of this pathology (OR=1.64, 95%CI 1.14-2.37, p=0.007; OR=4.48, 95%CI 1.20-16.80, p=0.02, and OR=1.57, 95%CI 1.05-2.36, p=0.03). In addition, NFKB1 allele -94del and genotype -94del/del were associated with advanced stages of the disease at the time of diagnosis (OR=0.66, 95%CI 0.46-0.97, p=0.03 and OR=0.43, 95%CI 0.20-0.92, p=0.03). These data suggest that -308G>A and -94ins>del polymorphisms of genes TNFA and NFKB1, respectively, can be involved in the pathogenesis of chronic lymphocytic leukemia.
Assuntos
Caspase 8/genética , Leucemia Linfocítica Crônica de Células B/genética , Subunidade p50 de NF-kappa B/genética , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de ProteçãoRESUMO
A biochip-based method was developed to identify the BCR-ABL mutations that affect the thyrosine kinase domain and determine resistance to targeted therapy with thyrosine kinase inhibitors. The method is based on RT-PCR followed by allele-specific hybridization on a biochip with immobilized oligonucleotide probes. The biochip addresses 11 mutations, which are responsible for up to 85% of imatinib resistance cases. A method to decect the clinically significant mutation T315I was designed on the basis of LNA-clamped PCR and proved highly sensitive, detecting the mutation in clinical samples with a leukemic cell content of 5% or higher. The method was validated using clinical samples from chronic myeloid leukemia (CML) patients with acquired resistance to imatinib. The results of hybridization on biochip were verified by Sanger sequencing.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Análise Mutacional de DNA , Dasatinibe/uso terapêutico , Feminino , Expressão Gênica , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
Relationship between interleukin-10 (IL-10) gene G-1082A (rs1800896) polymorphism and the risk of development and stages of chronic lymphoid leukemia is studied in ethnic Russian residents of the Kirov region of Russia. Associations of allele -1082A and genotypes (-1082AA/-1082AG) with the risk of chronic lymphoid leukemia are detected (OR=1.39, 95%CI=1.09-1.78 and OR=1.66, 95%CI=1.09-2.54, respectively). In addition, association of 1082AA genotype with late stages of the disease by the moment of diagnosis is detected. These data indicate that IL-10 polymorphism G-1082A may be involved in the pathogenesis of chronic lymphoid leukemia.
Assuntos
Interleucina-10/genética , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , População BrancaRESUMO
The effects of GSTM1 and GSTT1 gene deletion ("zero") polymorphisms on the risk of chronic myeloid leukemia development and progress and on response to imatinib monotherapy were studied in the representatives of the Russian nationality in the Vyatka region of Russia. Homozygotic carriership of GSTT1 "zero" allele was associated with a 3.66 times higher risk of chronic myeloid leukemia development in residents of the Vyatka region (OR=3.66, 95% CI=2.12-6.30; p<0.0001). Combinations of the "zero" GSTM1 and GSTT1 genotypes were risk factors indicating the probable disease progress and failure of high cytogenetic response after 12 months of imatinib therapy (400 mg daily).
