title: Activating mutations affecting the NF-kappa B pathway and EZH2-mediated epigenetic regulation are rare events in primary mediastinal large B-cell lymphoma.
abstract: BACKGROUND
  Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of diffuse large B-cell lymphoma (DLBCL) frequently observed in young patients. High-dose immunochemotherapy constitutes the current therapeutic gold-standard, despite significant toxicity and serious late effects. Several hotspots harboring oncogenic gain-of-function mutations were recently shown to pose vital hallmarks in activated B-cell like (ABC-) (CD79B, CARD11 and MYD88) and germinal center like (GCB-) DLBCL (EZH2), respectively. Several promising targeted-therapy approaches, derived from these findings, are currently under development.
  
  
  METHODS
  We thoroughly characterized a cohort of 25 untreated patients with de novo PMBL by immunohistochemical and cytogenetic means and assessed the prevalence of activating mutations affecting EZH2, CD79B and CARD11 utilizing a polymerase chain reaction (PCR)-based capillary sequencing approach. Moreover, the MYD88 p. L265P status was assessed by employing a pyrosequencing approach.
  
  
  RESULTS
  PMBLs included in this study did not harbor any of the reported hotspot mutations activating the nuclear factor (NF)-kappa B signaling cascade or the EZH2-mediated epigenetic deregulation of gene expression. Immunohistochemical characterization revealed an ABC phenotype in 44% (n=11) of cases.
  
  
  CONCLUSIONS
  We report that genetic alterations of these genes are rare events in PMBL unlike other subtypes of DLBCL. Our findings suggest that a substantial subset of PMBL patients may benefit from treatment approaches targeting BCR-mediated activation of NF-kappa B.
authors.affiliation: Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany niklas.gebauer@medizin.uni-luebeck.de.
authors.forename: Niklas
authors.initials: N
authors.lastname: Gebauer
authors.affiliation: Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Tim Tristan
authors.initials: TT
authors.lastname: Hardel
authors.affiliation: Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Gebauer
authors.affiliation: Department of Pathology-Reference Centre for Lymph Node Pathology and Hematopathology, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Veronica
authors.initials: V
authors.lastname: Bernard
authors.affiliation: Department of Pathology-Reference Centre for Lymph Node Pathology and Hematopathology, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Merz
authors.affiliation: Department of Pathology-Reference Centre for Lymph Node Pathology and Hematopathology, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Alfred C
authors.initials: AC
authors.lastname: Feller
authors.affiliation: Department of Radiation Oncology, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Rades
authors.affiliation: Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Biersack
authors.affiliation: Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
authors.affiliation: Department of Pathology-Reference Centre for Lymph Node Pathology and Hematopathology, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thorns
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008479:Mediastinal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D016328:NF-kappa B / Q000378:metabolism*; D009857:Oncogenes; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D016328:NF-kappa B; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: CARD11; CD79B; EZH2; MYD88; NFkappaB pathway; Primary mediastinal large B-cell lymphoma