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

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Authors	YOUNG E. NOERENBERG D. MANSOURI L. LJUNGSTROM V. FRICK M. SUTTON L. A. BLAKEMORE S. J. GALAN-SOUSA J. PLEVOVÁ Karla BALIAKAS P. ROSSI D. CLIFFORD R. ROOS-WEIL D. NAVRKALOVÁ Veronika DOERKEN 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. POSPÍŠILOVÁ Šárka ZENZ T. OAKES C. C. STREFFORD J. C. ROSENQUIST R. DAMM F.
Year of publication	2017
Type	Article in Periodical
Magazine / Source	Leukemia
MU Faculty or unit	Central European Institute of Technology
Citation
Web	http://www.nature.com/leu/journal/v31/n7/full/leu2016359a.html?foxtrotcallback=true
Doi	http://dx.doi.org/10.1038/leu.2016.359
Field	Oncology and hematology
Keywords	IDENTIFIES RECURRENT MUTATIONS; LRF CLL4 TRIAL; GENE-MUTATIONS; MYELODYSPLASTIC SYNDROMES; TRANSCRIPTION FACTORS; CLONAL EVOLUTION; SF3B1 MUTATIONS; HIGH-THROUGHPUT; ATM MUTATIONS; NOTCH1
Description	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.
Related projects:	Vliv selekce genomických poškození na průběh chronické lymfocytární leukémie CEITEC 2020