title: EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia.
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.
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Young
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Noerenberg
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Mansouri
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: V
authors.initials: V
authors.lastname: Ljungström
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Frick
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: L-A
authors.initials: LA
authors.lastname: Sutton
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Blakemore
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Galan-Sousa
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Plevova
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Baliakas
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.|Hematology, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: R
authors.initials: R
authors.lastname: Clifford
authors.affiliation: INSERM, U1170, Institut Gustave Roussy, Villejuif, France.
authors.forename: D
authors.initials: D
authors.lastname: Roos-Weil
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Navrkalova
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Dörken
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
authors.forename: C A
authors.initials: CA
authors.lastname: Schmitt
authors.affiliation: Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, and Hematology Center, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: K E
authors.initials: KE
authors.lastname: Smedby
authors.affiliation: Department of Laboratory Medicine, Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Juliusson
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Giacopelli
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Blachly
authors.affiliation: Hematology Department, General Hospital of Nikea, Piraeus, Greece.
authors.forename: C
authors.initials: C
authors.lastname: Belessi
authors.affiliation: First Department of Propaedeutic Medicine, School of Medicine, University of Athens, Athens, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Panagiotidis
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: N
authors.identifier: 0000-0003-1023-6650
authors.initials: N
authors.lastname: Chiorazzi
authors.affiliation: Laboratory of Hematology and Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Davi
authors.affiliation: Department of Immunology, Laboratory for Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: A W
authors.initials: AW
authors.lastname: Langerak
authors.affiliation: Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
authors.forename: D
authors.initials: D
authors.lastname: Oscier
authors.affiliation: Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: A
authors.initials: A
authors.lastname: Schuh
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Università Vita-Salute San Raffaele, Milan, Italy.|Division of Experimental Oncology and Department of Onco-Hematology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
authors.forename: P
authors.identifier: 0000-0003-3750-7342
authors.initials: P
authors.lastname: Ghia
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Fan
authors.affiliation: INSERM, U1170, Institut Gustave Roussy, Villejuif, France.
authors.forename: O A
authors.initials: OA
authors.lastname: Bernard
authors.affiliation: Laboratory of Hematology and Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Nguyen-Khac
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California at San Diego/Moores Cancer Center, La Jolla, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Rassenti
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California at San Diego/Moores Cancer Center, La Jolla, CA, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Sweden.|Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: K
authors.initials: K
authors.lastname: Stamatopoulos
authors.affiliation: Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
authors.forename: S
authors.initials: S
authors.lastname: Pospisilova
authors.affiliation: 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.|Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.|German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Zenz
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Oakes
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Strefford
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.|German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.|Berlin Institute of Health (BIH), Berlin, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Damm
mesh_terms: D000328:Adult; D000368:Aged; D051767:Early Growth Response Protein 2 / Q000235:genetics*; D005260:Female; D016158:Genes, p53; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016016:Proportional Hazards Models
chemical_list: C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2