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