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

Urban Novak1, Andrea Rinaldi, Ivo Kwee

  • 1Institute for Cancer Genetics, Departments of Pathology and Genetics & Development, and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.

Blood
|March 5, 2009
PubMed

Insights

Inactivating mutations and deletions of the TNFAIP3 (A20) gene are common in marginal zone lymphomas (MZLs). This genetic aberration may drive lymphomagenesis by promoting NF-kappaB activation.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Cytogenetic abnormalities are observed in marginal zone lymphomas (MZLs) originating from various sites.
  • Homozygous deletions of TNFAIP3 (A20) at 6q23, a negative regulator of NF-kappaB, were previously identified in ocular adnexal MZL, suggesting its tumor suppressor role.

Purpose of the Study:

  • To investigate the inactivation of the TNFAIP3 (A20) gene through DNA mutations or deletions across different subtypes of MZL.
  • To determine the frequency and spectrum of A20 alterations in extranodal MZL (EMZL), nodal MZL (NMZL), and splenic MZL (SMZL).

Main Methods:

  • Analysis of DNA mutations and deletions in a cohort of 32 MZL samples.
  • Utilized fluorescent in situ hybridization (FISH) and single nucleotide polymorphism (SNP)-arrays to detect A20 deletions.
  • Sequencing to identify inactivating mutations encoding truncated A20 proteins.

Main Results:

  • Inactivating mutations in A20 were found in 19% (6/32) of MZLs, including EMZL (18%), NMZL (33%), and SMZL (8%).
  • Two additional MZLs without mutations exhibited monoallelic or biallelic A20 deletions.
  • A20 inactivation occurs across various MZL subtypes.

Conclusions:

  • Inactivation of the TNFAIP3 (A20) gene, via mutation or deletion, is a frequent event in marginal zone lymphomas.
  • A20 inactivation may contribute to lymphomagenesis by leading to constitutive NF-kappaB activation.
  • These findings highlight A20 as a potential tumor suppressor and therapeutic target in MZL.

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