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. 2009 May 14;113(20):4918-21.
doi: 10.1182/blood-2008-08-174110. Epub 2009 Mar 3.

The NF-{kappa}B negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas

Urban Novak  1 , Andrea Rinaldi, Ivo Kwee, Subhadra V Nandula, Paola M V Rancoita, Mara Compagno, Michaela Cerri, Davide Rossi, Vundavalli V Murty, Emanuele Zucca, Gianluca Gaidano, Riccardo Dalla-Favera, Laura Pasqualucci, Govind Bhagat, Francesco Bertoni
Affiliations

The NF-{kappa}B negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas

Urban Novak et al. Blood. .

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.

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Figures

Figure 1
Figure 1
Inactivation of A20 by mutation and deletion. (A) Representative chromatograms of A20 exon 7 genomic sequences obtained by direct sequencing of tumor and matched normal DNA from a nodal MZL (case 18-C), with a 1-bp somatic insertion leading to a frameshift. Positions according to reference sequence NM_006290.2. (B) Dual-color FISH analysis of an extranodal MZL (case 9-C), hybridized with A20 probes (red) and a chromosome 6 centromeric probe (green). Red arrows indicate cells with homozygous A20 deletions; white arrows point to cells with a normal signal pattern. (Three hundred cells were analyzed, fluorescence signals were captured after staining with 4′-6-diamidino-2-phenylindole [DAPI] using the Cytovision Imaging System [Applied Imaging, Santa Clara, CA] attached to a Nikon Eclipse 600 microscope 100×/1.40 NA oil objective [Nikon Instruments, Melville, NY.])
Figure 2
Figure 2
Mono- and bi-allelic inactivation of A20 in MZL. (A) Distribution and features of A20 mutations in MZL. Schematic representation of the human A20 protein with its functional domains (OTU indicates ovarian tumor domain, mediating the deubiquitinating activity of A20; ZF, zinc-finger domain, exerting the ubiquitin ligase activity of A20); the cleavage site of A20 by the MALT1 protease is also indicated. The approximate location of A20 mutations is indicated below the map with triangles, and the types of mutations are described in detail in the table. *In these cases, the somatic origin of the mutation was confirmed by analysis of matched normal DNA. (B) Frequencies of A20 mutations and genetic loss in MZL subtypes. (C) Allelic distribution of A20 inactivation by mutations and deletions and known recurrent cytogenetic aberrations for all MZL cases analyzed. Each column represents 1 case, and the sites of the EMZL are indicated.
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