title: Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma.
abstract: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)-a subtype of Hodgkin lymphoma (HL)-is characterized by a low content of tumor cells, the lymphocyte predominant (LP) cells. Transformation into diffuse large B-cell lymphoma (DLBCL) occurs in about 10% of patients. We performed whole-genome mutation analysis of the DLBCL components from two composite lymphomas consisting of clonally related NLPHL and DLBCL as a means to identify candidate tumor suppressor genes and oncogenes in NLPHL. The analysis of LP cells for selected mutations of the DLBCL revealed that most mutations are also present in the LP cells, indicating a close relationship between the two components. The analysis of 62 selected genes in NLPHL by targeted ultra-deep sequencing revealed three novel highly recurrently mutated genes (each mutated in ~50% of cases), that is, DUSP2, SGK1 and JUNB. SGK1 was expressed in the LP cells of primary NLPHL cases and in the NLPHL cell line DEV. Administration of an SGK1 inhibitor induced apoptosis in the NLPHL cell line DEV and the DLBCL cell line Farage, suggesting a pathogenetic role of SGK1 in the LP and DLBCL cells. In summary, the present study identifies SGK1, DUSP2 and JUNB as novel key players in the pathogenesis of NLPHL.
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schuhmacher
authors.affiliation: GeneCore, European Molecular Biology Laboratory, Heidelberg, Germany.|Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Rausch
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Fuller
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Döring
authors.affiliation: Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weniger
authors.affiliation: Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Lollies
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Weiser
authors.affiliation: José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Thurner
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Rengstl
authors.affiliation: Department of Internal Medicine 2, Hospital of The J. W. Goethe University, Frankfurt, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Brunnberg
authors.affiliation: Department of Pathology, Tampere University Hospital, University of Tampere, Tampere, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Vornanen
authors.affiliation: José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pfreundschuh
authors.affiliation: GeneCore, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Benes
authors.affiliation: Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.|The German Cancer Consortium (DKTK), Essen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Küppers
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Newrzela
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: M-L
authors.initials: ML
authors.lastname: Hansmann
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D054641:Dual Specificity Phosphatase 2 / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D016130:Immunophenotyping; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008224:Lymphoma, Follicular / Q000235:genetics / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D054641:Dual Specificity Phosphatase 2; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D000099184:Serum-Glucocorticoid Regulated Kinases; C581727:JunB protein, human; C517032:DUSP2 protein, human