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

Young, E, Noerenberg, D, Mansouri, L, Ljungström, V, Frick, M, Sutton, L-A, Blakemore, S J, Galan-Sousa, J, Plevova, K, Baliakas, P, Rossi, D, Clifford, R, Roos-Weil, D, Navrkalova, V, Dörken, B, Schmitt, C A, Smedby, K E, Juliusson, G, Giacopelli, B, Blachly, J S, Belessi, C, Panagiotidis, P, Chiorazzi, N, Davi, F, Langerak, A W, Oscier, D, Schuh, A, Gaidano, G, Ghia, P, Xu, W, Fan, L, Bernard, O A, Nguyen-Khac, F, Rassenti, L, Li, J, Kipps, T J, Stamatopoulos, K, Pospisilova, S, Zenz, T, Oakes, C C, Strefford, J C, Rosenquist, R and Damm, F (2017) EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia. Leukemia, 31, 1547–1554. (doi:10.1038/leu.2016.359).

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.Leukemia advance online publication, 3 January 2017; doi:10.1038/leu.2016.359.

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Contributors

Author: J C Strefford

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