Unknown,Transcriptomics,Genomics,Proteomics

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A20 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-kappa B, were described in ocular adnexal MZL, suggesting a role for A20 as a tumor suppressor in this disease entity. Here, we investigated inactivation of A20 by DNA mutations or deletions in a panel of extranodal (EMZL), nodal (NMZL) and splenic (SMZL) MZLs. Inactivating mutations encoding truncated A20 proteins were identified in 6/32 (18.8%) MZLs, including 3/11 (27.3%) EMZLs, 2/9 (22.2%) NMZLs, and 1/12 (8.3%) SMZLs. Two additional unmutated non-splenic MZLs also showed mono- or biallelic A20 deletions by FISH and/or array-CGH. Thus, A20 loss by both somatic mutations and/or deletions represents a common genetic aberration across all MZL subtypes, which may contribute to lymphomagenesis by inducing constitutive NF-kappa B activation. Keywords: Genome variation profiling by SNP array 27 MZL samples. No technical replications.

ORGANISM(S): Homo sapiens

SUBMITTER: Francesco Bertoni

PROVIDER: E-GEOD-13989 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Novak Urban U Rinaldi Andrea A Kwee Ivo I Nandula Subhadra V SV Rancoita Paola M V PM Compagno Mara M Cerri Michaela M Rossi Davide D Murty Vundavalli V VV Zucca Emanuele E Gaidano Gianluca G Dalla-Favera Riccardo R Pasqualucci Laura L Bhagat Govind G Bertoni Francesco F

Blood 20090303 20

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 extran ...[more]

PMID: 19258598

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Project description:Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal center B cell-like (GCB) and activated B cell like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kB transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-kB activation in these tumors represents an intrinsic program of the tumor cell of origin or a pathogenetic event. Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations at multiple genes, including negative (TNFAIP3/A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7/TAK1 and TNFRSF11A/RANK) regulators of NF-kB. Of these, the A20 gene, which encodes for a ubiquitin-modifying enzyme involved in termination of NF-kB responses, is the most commonly affected one, with ~30% of the patients displaying biallelic inactivation by mutations and/or deletions, suggesting a tumor suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kB. Thus, our results demonstrate that NF-kB activation in DLBCL is caused by genetic lesions affecting multiple genes, whose loss or activation may promote lymphomagenesis by leading to abnormally prolonged NF-kB responses. We show that most ABC-DLBCL and a smaller fraction of GCB-DLBCL display genetic lesions affecting multiple NFkB pathway genes, with A20 representing the most frequently mutated gene Experiment Overall Design: DLBCL biopsies from 73 patients were collected from the archives of the Departments of Pathology at Columbia University and Weill Cornell Medical College. Total RNA was extracted from frozen tumor biopsies and processed according to Affymetrix standard protocols. Purified tonsillar geminal center cells (centroblasts and centrocytes, 5 samples each from different individuals) were purified by magnetic cell separation as described in Klein et al, PNAS 2003.

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Dataset Information

A20 IN MARGINAL ZONE LYMPHOMAS

Publications

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

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