title: Mutations of CARD11 but not TNFAIP3 may activate the NF-kappaB pathway in primary CNS lymphoma.
abstract: Primary CNS lymphoma (PCNSL), the intracerebral subgroup of diffuse large B cell lymphoma (DLBCL), shows evidence for aberrant activation of the nuclear factor (NF)-kappaB pathway. In order to identify potential activators of the NF-kappaB complex, we analyzed the CARD11 and TNFAIP3 genes for the presence of somatic mutations and TNFAIP3 for aberrant promoter methylation in PCNSL. We also compared PCNSL to spinal DLBCL, because CARD11 and TNFAIP3 mutations have been described in systemic DLBCL. CARD11 mutations, located in the coiled-coil region, which may activate NF-kappaB, were detected in 16% (5/32) of PCNSL, while TNFAIP3 mutations were detected in 3% (1/32) of PCNSL. In PCNSL, all CARD11 mutations were heterozygous, in-frame, induced amino acid exchanges, and presumably led to activation of this oncogene. Spinal DLBCL harbored mutations of CARD11 and TNFAIP3 in 10% (1/10) and 20% (2/10) of cases, respectively. In both PCNSL and spinal DLBCL, mutations in CARD11 and TNFAIP3 were mutually exclusive. TNFAIP3 was unmethylated in all PCNSLs (30/30) and spinal DLBCLs (10/10). We conclude that mutations of the oncogene CARD11 may contribute to NF-kappaB activation and thereby play a role in the pathogenesis of PCNSL, while, in contrast to systemic DLBCL, inactivation of TNFAIP3 either by mutation or methylation seems to be of minor significance.
authors.affiliation: Department of Neuropathology, University Hospital Cologne, 50924 Cologne, Germany. m.montesinos-rongen@uni-koeln.de
authors.forename: Manuel
authors.initials: M
authors.lastname: Montesinos-Rongen
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitz
authors.forename: Anna
authors.initials: A
authors.lastname: Brunn
authors.forename: Stefan
authors.initials: S
authors.lastname: Gesk
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.forename: Ke
authors.initials: K
authors.lastname: Hong
authors.forename: Otmar D
authors.initials: OD
authors.lastname: Wiestler
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
authors.forename: Martina
authors.initials: M
authors.lastname: Deckert
mesh_terms: D000328:Adult; D000368:Aged; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D016543:Central Nervous System Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006162:Guanylate Cyclase / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008223:Lymphoma / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D055815:Young Adult
chemical_list: D053468:CARD Signaling Adaptor Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011506:Proteins; C426747:TNIP3 protein, human; C426242:CARD11 protein, human; D006162:Guanylate Cyclase