Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma.
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.
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Larry
L
Mansouri
Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
Daniel
D
Noerenberg
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Emma
E
Young
Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
Elena
E
Mylonas
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Maysaa
M
Abdulla
Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
Mareike
M
Frick
Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Fazila
F
Asmar
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Viktor
V
Ljungström
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
Markus
M
Schneider
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kenichi
K
Yoshida
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Aron
A
Skaftason
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Tatjana
T
Pandzic
Department of Pathology, Hospital Clinic and Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
Blanca
B
Gonzalez
Hematopathology Department, Evangelismos Hospital, Athens, Greece.
Anna
A
Tasidou
Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
Nils
N
Waldhueter
Hematology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Alfredo
A
Rivas-Delgado
Department of Haematology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
Maria
M
Angelopoulou
Institute for Medical Informatics, Statistics, and Epidemiology, University at Leipzig, Leipzig, Germany.
Marita
M
Ziepert
Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
Christopher Maximilian
CM
Arends
Service d'Hématologie Adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.
Lucile
L
Couronné
Institute of Pathology, Charité, University Medical Center, Berlin, Germany.
Dido
D
Lenze
Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
Claudia D
CD
Baldus
INSERM U918, Université de Rouen, Centre Henri Becquerel, Rouen, France.
Christian
C
Bastard
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Jessica
J
Okosun
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Jude
J
Fitzgibbon
Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
Bernd
B
Dörken
Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
Hans G
HG
Drexler
Université Paris-Sud, Orsay, France.|INSERM, U1170, Institut Gustave Roussy, Villejuif, France.|Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France.
Damien
D
Roos-Weil
Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
Clemens A
CA
Schmitt
Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Helga D
HD
Munch-Petersen
Departments of Molecular Therapy in Haematology and Oncology and Translational Oncology, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany.|Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.|German Consortium for Translational Cancer Research, Heidelberg, Germany.
Thorsten
T
Zenz
Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.
Martin-Leo
ML
Hansmann
Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
Jonathan C
JC
Strefford
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Gunilla
G
Enblad
Université Paris-Sud, Orsay, France.|INSERM, U1170, Institut Gustave Roussy, Villejuif, France.|Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France.
Olivier A
OA
Bernard
Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Elisabeth
E
Ralfkiaer
Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
Martin
M
Erlanson
Department of Pathology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
Penelope
P
Korkolopoulou
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Magnus
M
Hultdin
Hematopathology Department, Evangelismos Hospital, Athens, Greece.
Theodora
T
Papadaki
Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Kirsten
K
Grønbæk
Hematology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Armando
A
Lopez-Guillermo
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Seishi
S
Ogawa
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
Ralf
R
Küppers
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
Kostas
K
Stamatopoulos
Hematology Department and Hematopoietic Cell Transplantation Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
Niki
N
Stavroyianni
Hematopathology Department, Evangelismos Hospital, Athens, Greece.
George
G
Kanellis
Institute of Pathology, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
Andreas
A
Rosenwald
Department of Pathology, Hospital Clinic and Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
Elias
E
Campo
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Rose-Marie
RM
Amini
Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany.|Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; and.
German
G
Ott
Department of Haematology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
Theodoros P
TP
Vassilakopoulos
Institute of Pathology, Charité, University Medical Center, Berlin, Germany.
Michael
M
Hummel
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Richard
R
Rosenquist
Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.|Berlin Institute of Health, Berlin, Germany.
Frederik
F
Damm
D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D017353:Gene Deletion; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000401:mortality; D008297:Male; D008479:Mediastinal Neoplasms / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015996:Survival Rate
D014408:Biomarkers, Tumor; D020672:I-kappa B Proteins; C105627:NFKBIE protein, human; D011518:Proto-Oncogene Proteins