title: Recurrent mutations in NF-κB pathway components, KMT2D, and NOTCH1/2 in ocular adnexal MALT-type marginal zone lymphomas.
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.
authors: Department of Haematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.|Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen, Essen, Germany.
authors: Patricia
authors: P
authors: Johansson
authors: Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen, Essen, Germany.
authors: Ludger
authors: L
authors: Klein-Hitpass
authors: Institute of Pathology and Neuropathology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen, Essen, Germany.|German Cancer Consortium (DKTK), Essen, Germany.
authors: Florian
authors: F
authors: Grabellus
authors: Center for Pathology Essen-Mitte, Essen, Germany.
authors: Georg
authors: G
authors: Arnold
authors: Department of Pathology, Haematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrecht University, Kiel, Germany.
authors: Wolfram
authors: W
authors: Klapper
authors: Department of Oral and Cranio-Maxillofacial Surgery, Kliniken Essen-Mitte, Evang. Huyssens-Stiftung/Knappschaft GmbH, University Hospital of Essen, Essen, Germany.
authors: Roman
authors: R
authors: Pförtner
authors: Department of Haematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: Ulrich
authors: U
authors: Dührsen
authors: Department of Ophthalmology, Molecular Ophthalmology Group, University of Duisburg-Essen, Essen, Germany.
authors: Anja
authors: A
authors: Eckstein
authors: Department of Haematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.|German Cancer Consortium (DKTK), Essen, Germany.
authors: Jan
authors: J
authors: Dürig
authors: Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen, Essen, Germany.|German Cancer Consortium (DKTK), Essen, Germany.
authors: Ralf
authors: R
authors: Küppers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D017209:Apoptosis; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic; D005134:Eye Neoplasms / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics*; D051883:Receptor, Notch2 / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D016328:NF-kappa B; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; D009363:Neoplasm Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2
keywords: KMT2D; MALT lymphoma; NF-κB; NOTCH; ocular adnexal lymphoma