학술논문
EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia
Document Type
article
Author
Young, E; Noerenberg, D; Mansouri, L; Ljungström, V; Frick, M; Sutton, L-A; Blakemore, SJ; Galan-Sousa, J; Plevova, K; Baliakas, P; Rossi, D; Clifford, R; Roos-Weil, D; Navrkalova, V; Dörken, B; Schmitt, CA; Smedby, KE; Juliusson, G; Giacopelli, B; Blachly, JS; Belessi, C; Panagiotidis, P; Chiorazzi, N; Davi, F; Langerak, AW; Oscier, D; Schuh, A; Gaidano, G; Ghia, P; Xu, W; Fan, L; Bernard, OA; Nguyen-Khac, F; Rassenti, L; Li, J; Kipps, TJ; Stamatopoulos, K; Pospisilova, S; Zenz, T; Oakes, CC; Strefford, JC; Rosenquist, R; Damm, F
Source
Leukemia. 31(7)
Subject
Language
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.