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Chronic lymphocytic leukemia

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

Leukemia volume 31, pages 1547–1554 (2017)Cite this article

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Abstract

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

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Acknowledgements

This study was supported by grants #2015_A09 from the Else-Kröner-Fresenius-Stiftung, #DA1787/1-1 from the Deutsche Forschungsgemeinschaft, the Lady Tata Memorial Trust (all F.D.), the Swedish Cancer Society, the Swedish Research Council, Uppsala University, Uppsala University Hospital, the Lion's Cancer Research Foundation, Uppsala, Marcus Borgström's Foundation, Uppsala, and Selander's Foundation, Uppsala, the research grants MSMT CR CEITEC2020 (LQ1601), and AZV MZCR 15-31834A/2015, H2020 ‘AEGLE, An analytics framework for integrated and personalized healthcare services in Europe’, and H2020 ‘MEDGENET, Medical Genomics and Epigenomics Network’ (No.692298), both funded by the European Commission. JCS was funded by Bloodwise (11052, 12036), the Kay Kendall Leukaemia Fund (873), Cancer Research UK (C34999/A18087, ECMC C24563/A15581), Wessex Medical Research and the Bournemouth Leukaemia Fund. This work was also supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the UK Department of Health's National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. FD is participant in the BIH-Charité Clinical Scientist Program funded by the Charité University Medical Center Berlin and the Berlin Institute of Health.

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Author notes

  1. E Young and D Noerenberg: Contributed equally as first authors.

  2. R Rosenquist and F Damm: Contributed equally as senior authors.

Authors and Affiliations

  1. Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Sweden

    E Young, L Mansouri, V Ljungström, L-A Sutton, P Baliakas, K Stamatopoulos & R Rosenquist

  2. Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany

    D Noerenberg, M Frick, J Galan-Sousa, B Dörken, C A Schmitt & F Damm

  3. Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

    S J Blakemore & J C Strefford

  4. Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic

    K Plevova, V Navrkalova & S Pospisilova

  5. Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    D Rossi & G Gaidano

  6. Hematology, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland

    D Rossi

  7. Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK

    R Clifford & A Schuh

  8. INSERM, U1170, Institut Gustave Roussy, Villejuif, France

    D Roos-Weil & O A Bernard

  9. Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, and Hematology Center, Karolinska University Hospital, Stockholm, Sweden

    K E Smedby

  10. Department of Laboratory Medicine, Stem Cell Center, Lund University, Lund, Sweden

    G Juliusson

  11. Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    B Giacopelli, J S Blachly & C C Oakes

  12. Hematology Department, General Hospital of Nikea, Piraeus, Greece

    C Belessi

  13. First Department of Propaedeutic Medicine, School of Medicine, University of Athens, Athens, Greece

    P Panagiotidis

  14. Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA

    N Chiorazzi

  15. Laboratory of Hematology and Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France

    F Davi & F Nguyen-Khac

  16. Department of Immunology, Laboratory for Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    A W Langerak

  17. Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK

    D Oscier

  18. Università Vita-Salute San Raffaele, Milan, Italy

    P Ghia

  19. Division of Experimental Oncology and Department of Onco-Hematology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy

    P Ghia

  20. Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China

    W Xu, L Fan & J Li

  21. Division of Hematology/Oncology, Department of Medicine, University of California at San Diego/Moores Cancer Center, La Jolla, CA, USA

    L Rassenti & T J Kipps

  22. Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece

    K Stamatopoulos

  23. Department of Molecular Therapy in Haematology and Oncology (G250) and Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany

    T Zenz

  24. Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany

    T Zenz

  25. German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany,

    T Zenz & F Damm

  26. Berlin Institute of Health (BIH), Berlin, Germany

    F Damm

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Correspondence to R Rosenquist.

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Young, E., Noerenberg, D., Mansouri, L. et al. EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia. Leukemia 31, 1547–1554 (2017). https://doi.org/10.1038/leu.2016.359

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