RESUMO
Genetic alterations causing constitutive activation of the nuclear factor kappa B (NF-κB) signaling pathway has been associated with the development of lymphomas. A20 (TNFAIP3) is a key regulator of NF-κB signaling. Its suppressor functions are often inactivated by deletions and/or mutations in various hematologic malignancies. Since we recently found the rs143002189 polymorphism in the A20 loci in our multiple myeloma samples, we further investigated this polymorphism in different lymphoid neoplasias. For this purpose, we tested 479 cases of the most common B cell malignancies for the presence of the rs143002189 polymorphism. We found a significant higher occurrence of the rs143002189 polymorphism in diffuse large B cell lymphoma (DLBCL) compared to non-neoplastic controls and other types of B cell malignancies. Furthermore, structure analyses of the mutated A20 protein led to the assumption that the new steric interaction within the protein is responsible for a reduced or inactivated A20 protein. Our data indicates that in a significant fraction of patients, rs143002189 might contribute to the development of DLBCL.
Assuntos
Linfoma Difuso de Grandes Células B/genética , Polimorfismo de Nucleotídeo Único , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Estudos de Casos e Controles , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Incidência , Linfoma Difuso de Grandes Células B/epidemiologia , Modelos Moleculares , Fases de Leitura AbertaRESUMO
Multiple myeloma (MM) is a malignant clonal expansion of plasma cells in the bone marrow and belongs to the mature B-cell neoplams. The pathogenesis of MM is associated with constitutive NF-κB activation. However, genetic alterations causing constitutive NF-κB activation are still incompletely understood. Since A20 (TNFAIP3) is a suppressor of the NF-κB pathway and is frequently inactivated in various lymphoid malignancies, we investigated the genetic and epigenetic properties of A20 in MM. In total, of 46 patient specimens analyzed, 3 single base pair exchanges, 2 synonymous mutations and one missense mutation were detected by direct sequencing. Gene copy number analysis revealed a reduced A20 gene copy number in 8 of 45 (17.7%) patients. Furthermore, immunohistochemical staining confirmed that A20 expression correlates with the reduction of A20 gene copy number. These data suggest that A20 contributes to tumor formation in a significant fraction of myeloma patients.
