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¹ Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, 45122 Essen, Germany
² Senkenberg Institute of Pathology, University of Frankfurt/Main, 60590 Frankfurt, Germany
³ Institute of Human Genetics and ⁴ Department of Pathology, Hematopathology Section and Lymph Node Registry, Christian-Albrechts University Kiel, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
⁵ Institute of Pathology, University of Heidelberg, 69120 Heidelberg, Germany
⁶ Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland

CORRESPONDENCE Ralf Küppers: ralf.kueppers{at}uk-essen.de

Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (cHL), are dependent on constitutive activation of nuclear factor B (NF-B). NF-B activation through various stimuli is negatively regulated by the zinc finger protein A20. To determine whether A20 contributes to the pathogenesis of cHL, we sequenced TNFAIP3, encoding A20, in HL cell lines and laser-microdissected HRS cells from cHL biopsies. We detected somatic mutations in 16 out of 36 cHLs (44%), including missense mutations in 2 out of 16 Epstein-Barr virus–positive (EBV⁺) cHLs and a missense mutation, nonsense mutations, and frameshift-causing insertions or deletions in 14 out of 20 EBV^– cHLs. In most mutated cases, both TNFAIP3 alleles were inactivated, including frequent chromosomal deletions of TNFAIP3. Reconstitution of wild-type TNFAIP3 in A20-deficient cHL cell lines revealed a significant decrease in transcripts of selected NF-B target genes and caused cytotoxicity. Extending the mutation analysis to primary mediastinal B cell lymphoma (PMBL), another lymphoma with constitutive NF-B activity, revealed destructive mutations in 5 out of 14 PMBLs (36%). This report identifies TNFAIP3 (A20), a key regulator of NF-B activity, as a novel tumor suppressor gene in cHL and PMBL. The significantly higher frequency of TNFAIP3 mutations in EBV^– than EBV⁺ cHL suggests complementing functions of TNFAIP3 inactivation and EBV infection in cHL pathogenesis.

© 2009 Schmitz et al.
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