Research Papers:

Recurrent mutations in NF-κB pathway components, KMT2D, and NOTCH1/2 in ocular adnexal MALT-type marginal zone lymphomas

Patricia Johansson, Ludger Klein-Hitpass, Florian Grabellus, Georg Arnold, Wolfram Klapper, Roman Pförtner, Ulrich Dührsen, Anja Eckstein, Jan Dürig and Ralf Küppers _

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Oncotarget. 2016; 7:62627-62639. https://doi.org/10.18632/oncotarget.11548

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Patricia Johansson1,2, Ludger Klein-Hitpass2, Florian Grabellus3,4,*, Georg Arnold5, Wolfram Klapper6, Roman Pförtner7, Ulrich Dührsen1, Anja Eckstein8, Jan Dürig1,4, Ralf Küppers2,4

1Department of Haematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

2Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen, Essen, Germany

3Institute of Pathology and Neuropathology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen, Essen, Germany

4German Cancer Consortium (DKTK), Essen, Germany

5Center for Pathology Essen-Mitte, Essen, Germany

6Department of Pathology, Haematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrecht University, Kiel, Germany

7Department of Oral and Cranio-Maxillofacial Surgery, Kliniken Essen-Mitte, Evang. Huyssens-Stiftung/Knappschaft GmbH, University Hospital of Essen, Essen, Germany

8Department of Ophthalmology, Molecular Ophthalmology Group, University of Duisburg-Essen, Essen, Germany

*Present address: Center for Pathology Essen-Mitte, Essen, Germany

Correspondence to:

Ralf Küppers, email: [email protected]

Keywords: KMT2D, MALT lymphoma, NF-κB, NOTCH, ocular adnexal lymphoma

Received: April 06, 2016    Accepted: August 10, 2016    Published: August 23, 2016


The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is still poorly understood. We analyzed 63 cases of such lymphomas for non-synonymous mutations in 24 candidate genes by amplicon sequencing. We validated frequent mutations in the NF-κB regulators MYD88, TNFAIP3 and TNIP1 in OAML, but also identified recurrent mutations in several additional components of the NF-κB pathway, including BCL10 and NFKBIA. Overall, 60% of cases had mutations in at least one component of NF-κB signaling, pointing to a central role of its genetic deregulation in OAML pathogenesis. Mutations in NOTCH1 and NOTCH2 were each found in 8% of cases, indicating a pathogenetic function of these factors in OAML. KMT2D was identified as the first epigenetic regulator with mutations in OAML, being mutated in 22% of cases. Mutations in MYD88 were associated with an inferior disease-free survival. Overall, we identified here highly recurrent genetic lesions in components of the NF-κB pathway, of NOTCH1 and NOTCH2 as well as KMT2D in OAML and thereby provide major novel insights into the pathogenesis of this B cell malignancy.

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