TY - JOUR
TI - EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia
AU - Young, E.
AU - Noerenberg, D.
AU - Mansouri, L.
AU - Ljungström, V.
AU - Frick, M.
AU - Sutton, L.-A.
AU - Blakemore, S.J.
AU - Galan-Sousa, J.
AU - Plevova, K.
AU - Baliakas, P.
AU - Rossi, D.
AU - Clifford, R.
AU - Roos-Weil, D.
AU - Navrkalova, V.
AU - Dörken, B.
AU - Schmitt, C.A.
AU - Smedby, K.E.
AU - Juliusson, G.
AU - Giacopelli, B.
AU - Blachly, J.S.
AU - Belessi, C.
AU - Panagiotidis, P.
AU - Chiorazzi, N.
AU - Davi, F.
AU - Langerak, A.W.
AU - Oscier, D.
AU - Schuh, A.
AU - Gaidano, G.
AU - Ghia, P.
AU - Xu, W.
AU - Fan, L.
AU - Bernard, O.A.
AU - Nguyen-Khac, F.
AU - Rassenti, L.
AU - Li, J.
AU - Kipps, T.J.
AU - Stamatopoulos, K.
AU - Pospisilova, S.
AU - Zenz, T.
AU - Oakes, C.C.
AU - Strefford, J.C.
AU - Rosenquist, R.
AU - Damm, F.
JO - Leukemia Research
PY - 2017
VL - 31
TODO - 7
SP - 1547-1554
PB - Nature Publishing Group
SN - 0145-2126
TODO - 10.1038/leu.2016.359
TODO - ATM protein;  biological marker;  CD38 antigen;  early growth response factor 2;  Notch1 receptor;  protein p53;  early growth response factor 2;  EGR2 protein, human, adult;  advanced cancer;  aged;  antigen expression;  Article;  cancer patient;  cancer prognosis;  cancer screening;  cancer survival;  chronic lymphatic leukemia;  female;  gene frequency;  gene mutation;  groups by age;  human;  major clinical study;  male;  mutational analysis;  overall survival;  priority journal;  prognostic assessment;  sequence analysis;  time to treatment;  classification;  genetics;  Leukemia, Lymphocytic, Chronic, B-Cell;  middle aged;  mortality;  mutation;  proportional hazards model;  tumor suppressor gene, Adult;  Aged;  Early Growth Response Protein 2;  Female;  Genes, p53;  Humans;  Leukemia, Lymphocytic, Chronic, B-Cell;  Male;  Middle Aged;  Mutation;  Proportional Hazards Models
TODO - 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. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
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