title: Rare occurrence of biallelic CYLD gene mutations in classical Hodgkin lymphoma.
abstract: Survival of the malignant Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) is dependent on constitutive activation of the nuclear factor kappaB (NF-kappaB) transcription factor. The deubiquitinating enzyme CYLD is a negative regulator of NF-kappaB and known to function as a tumor suppressor. To determine whether CYLD mutations play a role in cHL pathogenesis, we sequenced the gene in cHL cell lines and microdissected HRS cells obtained from lymph-node biopsies. A biallelic inactivation by mutations was found in the cHL cell-line KM-H2. However, the other seven cHL cell lines analyzed and HRS cells of 10 primary cHL cases did not show any mutations. By interphase cytogenetics, a (sub)clonal biallelic CYLD deletion was observed by interphase cytogenetics in 1 of 29 primary cHL, whereas signal patterns indicating decreased CYLD copy numbers were observed in a total of 10 of 29 primary cases. Our results suggest that biallelic CYLD mutations are rarely involved in cHL pathogenesis. Nevertheless, it is remarkable that KM-H2 cells, besides the CYLD mutations, also carry inactivating mutations in the genes of two other NF-kappaB inhibitors, that is, NFKBIA and TNFAIP3, exemplifying that multiple lesions in regulators of this signaling pathway can likely cooperatively contribute to the strong NF-kappaB activity of these cells.
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schmidt
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitz
authors.forename: Maciej
authors.initials: M
authors.lastname: Giefing
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: Martin-Subero
authors.forename: Stefan
authors.initials: S
authors.lastname: Gesk
authors.forename: Inga
authors.initials: I
authors.lastname: Vater
authors.forename: Anne
authors.initials: A
authors.lastname: Massow
authors.forename: Ewerton
authors.initials: E
authors.lastname: Maggio
authors.forename: Markus
authors.initials: M
authors.lastname: Schneider
authors.forename: Martin-Leo
authors.initials: ML
authors.lastname: Hansmann
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D020869:Gene Expression Profiling; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007834:Lasers; D008297:Male; D042282:Microdissection; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016539:Reed-Sternberg Cells / Q000378:metabolism / Q000473:pathology*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D000072000:NF-KappaB Inhibitor alpha; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3