Lymphoma

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.

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Acknowledgements

We thank Sabine Albrecht, Smaro Soworka, Ottilja Buhr, Ekaterini Hadzoglou, Susanne Hansen, Elena Hartung, Julia Bein, Maria Kemele, Christina Jakobus, Ralf Lieberz, Christiane Wenk and the EMBL GeneCore sequencing team and the EMBL IT unit for excellent technical assistance. We thank Dr Frederike Schmid, Dr Friederike Schwartz and Dr Marc Seifert for helpful discussions. This project was supported by the Deutsche Forschungsgemeinschaft (grant HA6145/1-2). M-LH, CD and SN were supported by the Kassel Stiftung. RK and M-LH were supported by the German Cancer Consortium (DKTK), the BMBF (01KU1002F; International Cancer Genome consortium, ICGC) and the Wilhelm Sander Foundation (2014.136.1).

Author contributions

SH was involved in the study design, performed the research, analysis and interpretation of data and wrote the manuscript; BS, AL, MW, LF, CW, LT and BR performed the research, analysis and interpretation of data; CD and TR performed the biostatistical analysis and interpretation of NGS data; UB, MV and VB contributed the essential material and were involved in the interpretation of data; MP, RK and SN performed the analysis and interpretation of data, and were involved in drafting the manuscript; M-LH was involved in the study design, interpretation of data and drafting the manuscript.

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Correspondence to S Hartmann.

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Hartmann, S., Schuhmacher, B., Rausch, T. et al. Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma. Leukemia 30, 844–853 (2016). https://doi.org/10.1038/leu.2015.328

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