Bianca Schuhmacher1, Julia Bein1, Tobias Rausch2,3, Vladimir Benes2, Thomas Tousseyn4, Martine Vornanen5, Maurilio Ponzoni6, Randy Gascoyne7, Christian Steidl7, Ralf Küppers8,9, Martin-Leo Hansmann1,10, Sylvia Hartmann1,10
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, Leuven, Belgium, 5 Department of Pathology, Tampere University Hospital and University of Tampere, Tampere, Finland, 6 Unit of Lymphoid Malignancies, Department of Pathology, Scientific Institute San Raffaele, Milan, Italy, 7 Department of Pathology and Laboratory Medicine and the Centre for Lymphoid Cancer, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada, 8 Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany, 9 Deutsches Konsortium für Translationale Krebsforschung (DKTK), 10 Reference and Consultant Center for Lymphoma and Lymph Node Diagnostics, Goethe University, Frankfurt am Main, Germany
T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare aggressive lymphoma showing histological overlap with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). 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. The aim of our study was to analyze if genes recurrently mutated in NLPHL are also mutated in THRLBCL. A targeted re-sequencing approach for 67 genes revealed that the mutational landscapes of THRLBCL and NLPHL are highly related, both frequently harboring mutations in JUNB, DUSP2, SGK1, CREBBP and SOCS1. JUNB, DUSP2, SGK1 and SOCS1 showed an increased number of variants per case and were affected by mutations more frequently in THRLBCL and the histopathological NLPHL variants than in typical NLPHL. Mutations in these four genes were highly enriched for somatic hypermutation (SHM) hotspot sites, suggesting an important role of aberrant SHM in the pathogenesis of NLPHL and THRLBCL. THRLBCL and the histopathological NLPHL variants might therefore have longer or stronger exposure to SHM than typical NLPHL. Taken together, the present study further supports a close relationship of THRLBCL and NLPHL by showing that they share key highly recurrent genetic lesions.