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

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

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.

Journal Article
0887-6924
1547–1554
Young, E
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Noerenberg, D
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Mansouri, L
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Ljungström, V
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Frick, M
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Sutton, L-A
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Blakemore, S J
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Galan-Sousa, J
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Plevova, K
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Baliakas, P
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Rossi, D
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Clifford, R
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Roos-Weil, D
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Navrkalova, V
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Dörken, B
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Schmitt, C A
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Smedby, K E
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Juliusson, G
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Giacopelli, B
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Blachly, J S
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Belessi, C
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Panagiotidis, P
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Chiorazzi, N
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Davi, F
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Langerak, A W
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Oscier, D
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Schuh, A
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Gaidano, G
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Ghia, P
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Xu, W
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Fan, L
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Bernard, O A
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Nguyen-Khac, F
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Rassenti, L
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Li, J
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Kipps, T J
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Stamatopoulos, K
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Pospisilova, S
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Zenz, T
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Oakes, C C
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Strefford, J C
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Rosenquist, R
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Damm, F
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Young, E
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Noerenberg, D
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Mansouri, L
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Ljungström, V
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Frick, M
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Sutton, L-A
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Blakemore, S J
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Galan-Sousa, J
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Plevova, K
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Baliakas, P
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Rossi, D
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Clifford, R
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Roos-Weil, D
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Navrkalova, V
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Dörken, B
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Schmitt, C A
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Smedby, K E
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Juliusson, G
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Giacopelli, B
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Blachly, J S
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Belessi, C
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Panagiotidis, P
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Chiorazzi, N
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Davi, F
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Langerak, A W
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Oscier, D
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Schuh, A
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Gaidano, G
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Ghia, P
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Xu, W
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Fan, L
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Bernard, O A
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Nguyen-Khac, F
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Rassenti, L
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Li, J
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Kipps, T J
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Stamatopoulos, K
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Pospisilova, S
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Zenz, T
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Oakes, C C
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Strefford, J C
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Rosenquist, R
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Damm, F
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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).

Record type: Article

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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More information

Accepted/In Press date: 9 November 2016
e-pub ahead of print date: 3 January 2017
Published date: 3 January 2017
Keywords: Journal Article

Identifiers

Local EPrints ID: 413241
URI: https://eprints.soton.ac.uk/id/eprint/413241
ISSN: 0887-6924
PURE UUID: 00605de8-b7ff-4735-bafb-083c7464f19a
ORCID for J C Strefford: ORCID iD orcid.org/0000-0002-0972-2881

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Date deposited: 17 Aug 2017 16:31
Last modified: 10 Dec 2019 01:45

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Contributors

Author: E Young
Author: D Noerenberg
Author: L Mansouri
Author: V Ljungström
Author: M Frick
Author: L-A Sutton
Author: S J Blakemore
Author: J Galan-Sousa
Author: K Plevova
Author: P Baliakas
Author: D Rossi
Author: R Clifford
Author: D Roos-Weil
Author: V Navrkalova
Author: B Dörken
Author: C A Schmitt
Author: K E Smedby
Author: G Juliusson
Author: B Giacopelli
Author: J S Blachly
Author: C Belessi
Author: P Panagiotidis
Author: N Chiorazzi
Author: F Davi
Author: A W Langerak
Author: D Oscier
Author: A Schuh
Author: G Gaidano
Author: P Ghia
Author: W Xu
Author: L Fan
Author: O A Bernard
Author: F Nguyen-Khac
Author: L Rassenti
Author: J Li
Author: T J Kipps
Author: K Stamatopoulos
Author: S Pospisilova
Author: T Zenz
Author: C C Oakes
Author: J C Strefford ORCID iD
Author: R Rosenquist
Author: F Damm

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