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Blood. 2016 Dec 8;128(23):2666-2670. Epub 2016 Sep 26.

Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma.

Author information

1
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
2
Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
3
Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
4
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
5
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
6
Department of Pathology, Hospital Clinic and Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
7
Hematopathology Department, Evangelismos Hospital, Athens, Greece.
8
Hematology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.
9
Department of Haematology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
10
Institute for Medical Informatics, Statistics, and Epidemiology, University at Leipzig, Leipzig, Germany.
11
Service d'Hématologie Adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.
12
Institute of Pathology, Charité, University Medical Center, Berlin, Germany.
13
INSERM U918, Université de Rouen, Centre Henri Becquerel, Rouen, France.
14
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
15
Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
16
Université Paris-Sud, Orsay, France.
17
INSERM, U1170, Institut Gustave Roussy, Villejuif, France.
18
Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France.
19
Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
20
Departments of Molecular Therapy in Haematology and Oncology and Translational Oncology, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany.
21
Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
22
German Consortium for Translational Cancer Research, Heidelberg, Germany.
23
Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.
24
Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
25
Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
26
Department of Pathology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
27
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
28
Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
29
Hematology Department and Hematopoietic Cell Transplantation Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
30
Institute of Pathology, University of Würzburg, Würzburg, Germany.
31
Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
32
Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany.
33
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; and.
34
Berlin Institute of Health, Berlin, Germany.

Abstract

We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBε, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%]). NFKBIE-deleted PMBL patients were more often therapy refractory (P = .022) and displayed inferior outcome compared with wild-type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy (P =022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P = .003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

PMID:
27670424
DOI:
10.1182/blood-2016-03-704528
[Indexed for MEDLINE]
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