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Haematologica. 2019 Feb;104(2):330-337. doi: 10.3324/haematol.2018.203224. Epub 2018 Sep 13.

JUNB, DUSP2, SGK1, SOCS1 and CREBBP are frequently mutated in T-cell/histiocyte-rich large B-cell lymphoma.

Author information

1
Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.
2
Genecore, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
3
Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
4
Department of Pathology, University Hospitals K.U. Leuven, Belgium.
5
Department of Pathology, Tampere University Hospital and University of Tampere, Finland.
6
Unit of Lymphoid Malignancies, Department of Pathology, Scientific Institute San Raffaele, Milan, Italy.
7
José Carreras Center for Immuno and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg, Saar, Germany.
8
Department of Internal Medicine 2, Hospital of the J. W. Goethe University, Frankfurt am Main, Germany.
9
Department of Pathology and Laboratory Medicine and the Centre for Lymphoid Cancer, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada.
10
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
11
Deutsches Konsortium für Translationale Krebsforschung (DKTK), Germany.
12
Reference and Consultant Center for Lymphoma and Lymph Node Diagnostics, Goethe University, Frankfurt am Main, Germany.
13
Frankfurt Institute of Advanced Studies, Frankfurt am Main, Germany.
14
Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany s.hartmann@em.uni-frankfurt.de.

Abstract

T-cell/histiocyte-rich large B-cell lymphoma is a rare aggressive lymphoma showing histopathological overlap with nodular lymphocyte-predominant Hodgkin lymphoma. Despite differences in tumor microenvironment and clinical behavior, the tumor cells of both entities show remarkable similarities, suggesting that both lymphomas might represent a spectrum of the same disease. To address this issue, we investigated whether these entities share mutations. Ultra-deep targeted resequencing of six typical and 11 histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma, and nine cases of T-cell/histiocyte-rich large B-cell lymphoma revealed that genes recurrently mutated in nodular lymphocyte-predominant Hodgkin lymphoma are affected by mutations at similar frequencies in T-cell/histiocyte-rich large B-cell lymphoma. The most recurrently mutated genes were JUNB, DUSP2, SGK1, SOCS1 and CREBBP, which harbored mutations more frequently in T-cell/histiocyte-rich large B-cell lymphoma and the histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma than in its typical form. Mutations in JUNB, DUSP2, SGK1 and SOCS1 were highly enriched for somatic hypermutation hotspot sites, suggesting an important role of aberrant somatic hypermutation in the generation of these somatic mutations and thus in the pathogenesis of both lymphoma entities. Mutations in JUNB are generally rarely observed in malignant lymphomas and thus are relatively specific for nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma at such high frequencies (5/17 and 5/9 cases with JUNB mutations, respectively). Taken together, the findings of the present study further support a close relationship between T-cell/histiocyte-rich large B-cell lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma by showing that they share highly recurrent genetic lesions.

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