title: TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma.
abstract: 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 kappaB (NF-kappaB). NF-kappaB 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-kappaB target genes and caused cytotoxicity. Extending the mutation analysis to primary mediastinal B cell lymphoma (PMBL), another lymphoma with constitutive NF-kappaB activity, revealed destructive mutations in 5 out of 14 PMBLs (36%). This report identifies TNFAIP3 (A20), a key regulator of NF-kappaB 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.
authors.affiliation: Institute of Cell Biology (Cancer Research), Medical School, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitz
authors.forename: Martin-Leo
authors.initials: ML
authors.lastname: Hansmann
authors.forename: Verena
authors.initials: V
authors.lastname: Bohle
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: Martin-Subero
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hartmann
authors.forename: Gunhild
authors.initials: G
authors.lastname: Mechtersheimer
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.forename: Inga
authors.initials: I
authors.lastname: Vater
authors.forename: Maciej
authors.initials: M
authors.lastname: Giefing
authors.forename: Stefan
authors.initials: S
authors.lastname: Gesk
authors.forename: Jens
authors.initials: J
authors.lastname: Stanelle
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
mesh_terms: D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D020031:Epstein-Barr Virus Infections / Q000235:genetics; D016368:Frameshift Mutation; D016147:Genes, Tumor Suppressor; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014158:Transcription, Genetic; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3