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

• 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
• 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.

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