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.

1st Department of Propaedeutic Medicine School of Medicine University of Athens Athens Greece

Berlin Institute of Health Berlin Germany

Cancer Sciences Faculty of Medicine University of Southampton Southampton UK

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

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

Department of Hematology the 1st Affiliated Hospital of Nanjing Medical University Jiangsu Province Hospital Collaborative Innovation Center For Cancer Personalized Medicine Nanjing China

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

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

Department of Laboratory Medicine Stem Cell Center Lund University Lund Sweden

Department of Medicine 5 University Hospital Heidelberg Heidelberg Germany

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

Department of Molecular Pathology Royal Bournemouth Hospital Bournemouth UK

Department of Molecular Therapy in Haematology and Oncology Heidelberg Germany

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

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

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

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

German Consortium for Translational Cancer Research Heidelberg Germany

Hematology Department General Hospital of Nikea Piraeus Greece

Hematology Oncology Institute of Southern Switzerland and Institute of Oncology Research Bellinzona Switzerland

INSERM U1170 Institut Gustave Roussy Villejuif France

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

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

Laboratory of Hematology and Universite Pierre et Marie Curie Hopital Pitie Salpetriere Paris France

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

Università Vita Salute San Raffaele Milan Italy

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