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

E Young, D Noerenberg, L Mansouri, V Ljungström, M Frick, LA Sutton, SJ Blakemore, J Galan-Sousa, K Plevova, P Baliakas, D Rossi, R Clifford, D Roos-Weil, V Navrkalova, B Dörken, CA Schmitt, KE Smedby, G Juliusson, B Giacopelli, JS BlachlyC Belessi, P Panagiotidis, Nicholas Chiorazzi, F Davi, AW Langerak, D Oscier, A Schuh, G Gaidano, P Ghia, W Xu, L Fan, OA Bernard, F Nguyen-Khac, Laura Rassenti, J Li, TJ Kipps, K Stamatopoulos, S Pospisilova, T Zenz, CC Oakes, JC Strefford, R Rosenquist, F Damm

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)1547-1554
Number of pages8
JournalLeukemia
Volume31
Issue number7
DOIs
Publication statusPublished - 2017

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    Young, E., Noerenberg, D., Mansouri, L., Ljungström, V., Frick, M., Sutton, LA., 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., ... Damm, F. (2017). EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia. Leukemia, 31(7), 1547-1554. https://doi.org/10.1038/leu.2016.359