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Oncotarget. 2016 Sep 20;7(38):62627-62639. doi: 10.18632/oncotarget.11548.

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

Author information

1
Department of Haematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
2
Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen, Essen, Germany.
3
Institute of Pathology and Neuropathology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen, Essen, Germany.
4
German Cancer Consortium (DKTK), Essen, Germany.
5
Center for Pathology Essen-Mitte, Essen, Germany.
6
Department of Pathology, Haematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrecht University, Kiel, Germany.
7
Department of Oral and Cranio-Maxillofacial Surgery, Kliniken Essen-Mitte, Evang. Huyssens-Stiftung/Knappschaft GmbH, University Hospital of Essen, Essen, Germany.
8
Department of Ophthalmology, Molecular Ophthalmology Group, University of Duisburg-Essen, Essen, Germany.

Abstract

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.

KEYWORDS:

KMT2D; MALT lymphoma; NF-κB; NOTCH; ocular adnexal lymphoma

PMID:
27566587
PMCID:
PMC5308752
DOI:
10.18632/oncotarget.11548
[Indexed for MEDLINE]
Free PMC Article

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