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E. Young (Emma), Noerenberg, D. (D.), A. Mansouri (Ahmed), V. Ljungström (Viktor), Frick, M. (M.), L.-A. Sutton (L.), S.J. Blakemore (Stuart J.), Galan-Sousa, J. (J.), K. Plevova (K.), P. Baliakas (P.), et al. D. Rossi (Davide), R. Clifford (Ruth), D. Roos-Weil (Damien), V. Navrkalova (Veronika), Dörken, B. (B.), Schmitt, C.A. (C. A.), O. Smedby, G. Juliusson (Gunnar), Giacopelli, B. (B.), Blachly, J.S. (J. S.), C. Belessi (C.), P. Panagiotidis (P.), N. Chiorazzi (Nicholas), F. Davi (Frédéric), A.W. Langerak (Anton), D.G. Oscier (David Graham), A.H. Schuh (Anna), Gaidano, G. (G.), P. Ghia (Paolo), Xu, W. (W.), Fan, L. (L.), O.A. Bernard (O.), F. Nguyen-Khac (Florence), L. Rassenti (Laura), Li, J. (J.), Kipps, T.J. (T. J.), K. Stamatopoulos (Kostas), Pospisilova, S. (S.), Zenz, T. (T.), Oakes, C.C. (C. C.), J.C. Strefford (J.), R. Rosenquist (R.) and F. Damm (Frederik)

2017-07-01

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

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Publication

Leukemia , Volume 31 - Issue 7 p. 1547- 1554

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.

Additional Metadata
Persistent URL doi.org/10.1038/leu.2016.359, hdl.handle.net/1765/108390
Journal Leukemia
Grant This work was funded by the European Commission 7th Framework Programme; grant id h2020/692298 - Medical Genomics and Epigenomics Network (MEDGENET)
Organisation Department of Immunology
Citation
Young, E., Noerenberg, D. (D.), Mansouri, A., Ljungström, V., Frick, M. (M.), Sutton, L., … Damm, F. (2017). EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia. Leukemia, 31(7), 1547–1554. doi:10.1038/leu.2016.359


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