title: The NF-{kappa}B negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas.
abstract: Unique and shared cytogenetic abnormalities have been documented for marginal zone lymphomas (MZLs) arising at different sites. Recently, homozygous deletions of the chromosomal band 6q23, involving the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) gene, a negative regulator of NF-kappaB, were described in ocular adnexal MZL, suggesting a role for A20 as a tumor suppressor in this disease. Here, we investigated inactivation of A20 by DNA mutations or deletions in a panel of extranodal MZL (EMZL), nodal MZL (NMZL), and splenic MZL (SMZL). Inactivating mutations encoding truncated A20 proteins were identified in 6 (19%) of 32 MZLs, including 2 (18%) of 11 EMZLs, 3 (33%) of 9 NMZLs, and 1 (8%) of 12 SMZLs. Two additional unmutated nonsplenic MZLs also showed monoallelic or biallelic A20 deletions by fluorescent in situ hybridization (FISH) and/or SNP-arrays. Thus, A20 inactivation by either somatic mutation and/or deletion represents a common genetic aberration across all MZL subtypes, which may contribute to lymphomagenesis by inducing constitutive NF-kappaB activation.
authors.affiliation: Institute for Cancer Genetics, Departments of Pathology and Genetics & Development, and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
authors.forename: Urban
authors.initials: U
authors.lastname: Novak
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.forename: Ivo
authors.initials: I
authors.lastname: Kwee
authors.forename: Subhadra V
authors.initials: SV
authors.lastname: Nandula
authors.forename: Paola M V
authors.initials: PM
authors.lastname: Rancoita
authors.forename: Mara
authors.initials: M
authors.lastname: Compagno
authors.forename: Michaela
authors.initials: M
authors.lastname: Cerri
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Vundavalli V
authors.initials: VV
authors.lastname: Murty
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
mesh_terms: D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics*; D020125:Mutation, Missense / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3