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  • Title: Activating mutations affecting the NF-kappa B pathway and EZH2-mediated epigenetic regulation are rare events in primary mediastinal large B-cell lymphoma.
    Author: Gebauer N, Hardel TT, Gebauer J, Bernard V, Merz H, Feller AC, Rades D, Biersack H, Lehnert H, Thorns C.
    Journal: Anticancer Res; 2014 Oct; 34(10):5503-7. PubMed ID: 25275047.
    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. MATERIALS AND 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. CONCLUSION: 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.
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