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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Institute. NC. SEER stat fact sheets: chronic lymphocytic leukemia. Available at http://seer.cancer.gov/statfacts/html/clyl.html (accessed 15 May 2013).
Fabbri G, Dalla-Favera R . The molecular pathogenesis of chronic lymphocytic leukaemia. Nat Rev Cancer 2016; 16: 145–162.
Zenz T, Mertens D, Kuppers R, Dohner H, Stilgenbauer S . From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 2010; 10: 37–50.
Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014; 371: 213–223.
Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370: 997–1007.
Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016; 374: 311–322.
Sutton LA, Rosenquist R . The complex interplay between cell-intrinsic and cell-extrinsic factors driving the evolution of chronic lymphocytic leukemia. Semin Cancer Biol 2015; 34: 22–35.
Damm F, Nguyen-Khac F, Fontenay M, Bernard OA . Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies. Leukemia 2012; 26: 2027–2031.
Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.
Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–1847.
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK, Unmutated Ig V(H . genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–1854.
Sutton LA, Rosenquist R . Deciphering the molecular landscape in chronic lymphocytic leukemia: time frame of disease evolution. Haematologica 2015; 100: 7–16.
Puente XS, Bea S, Valdes-Mas R, Villamor N, Gutierrez-Abril J, Martin-Subero JI et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 2015; 526: 519–524.
Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J et al. Mutations driving CLL and their evolution in progression and relapse. Nature 2015; 526: 525–530.
Rodriguez D, Bretones G, Quesada V, Villamor N, Arango JR, Lopez-Guillermo A et al. Mutations in CHD2 cause defective association with active chromatin in chronic lymphocytic leukemia. Blood 2015; 126: 195–202.
Kampjarvi K, Jarvinen TM, Heikkinen T, Ruppert AS, Senter L, Hoag KW et al. Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia. Oncotarget 2015; 6: 1884–1888.
Mansouri L, Sutton LA, Ljungstrom V, Bondza S, Arngarden L, Bhoi S et al. Functional loss of IkappaBepsilon leads to NF-kappaB deregulation in aggressive chronic lymphocytic leukemia. J Exp Med 2015; 212: 833–843.
Ramsay AJ, Quesada V, Foronda M, Conde L, Martinez-Trillos A, Villamor N et al. POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia. Nat Genet 2013; 45: 526–530.
Ljungstrom V, Cortese D, Young E, Pandzic T, Mansouri L, Plevova K et al. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations. Blood 2016; 127: 1007–1016.
Parker H, Rose-Zerilli MJ, Larrayoz M, Clifford R, Edelmann J, Blakemore S et al. Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia. Leukemia 2016; 30: 2179–2186.
Jeromin S, Weissmann S, Haferlach C, Dicker F, Bayer K, Grossmann V et al. SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients. Leukemia 2014; 28: 108–117.
Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J et al. The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood 2013; 121: 468–475.
Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Dohner K et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014; 123: 3247–3254.
Baliakas P, Hadzidimitriou A, Sutton LA, Rossi D, Minga E, Villamor N et al. Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia 2015; 29: 329–336.
Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 2013; 121: 1403–1412.
Yasuda T, Sanjo H, Pages G, Kawano Y, Karasuyama H, Pouyssegur J et al. Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion. Immunity 2008; 28: 499–508.
Li S, Miao T, Sebastian M, Bhullar P, Ghaffari E, Liu M et al. The transcription factors Egr2 and Egr3 are essential for the control of inflammation and antigen-induced proliferation of B and T cells. Immunity 2012; 37: 685–696.
Herglotz J, Unrau L, Hauschildt F, Fischer M, Kriebitzsch N, Alawi M et al. Essential control of early B-cell development by Mef2 transcription factors. Blood 2016; 127: 572–581.
Damm F, Mylonas E, Cosson A, Yoshida K, Della Valle V, Mouly E et al. Acquired initiating mutations in early hematopoietic cells of CLL patients. Cancer Discov 2014; 4: 1088–1101.
Oakes CC, Seifert M, Assenov Y, Gu L, Przekopowitz M, Ruppert AS et al. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat Genet 2016; 48: 253–264.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111: 5446–5456.
Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007; 370: 230–239.
Damm F, Kosmider O, Gelsi-Boyer V, Renneville A, Carbuccia N, Hidalgo-Curtis C et al. Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood 2012; 119: 3211–3218.
Li H, Durbin R . Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 2010; 26: 589–595.
Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 2012; 22: 568–576.
Wang K, Li M, Hakonarson H . ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010; 38: qe164.
Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011; 365: 2497–2506.
Quesada V, Conde L, Villamor N, Ordonez GR, Jares P, Bassaganyas L et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 2011; 44: 47–52.
Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 2011; 208: 1389–1401.
Messina M, Del Giudice I, Khiabanian H, Rossi D, Chiaretti S, Rasi S et al. Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness. Blood 2014; 123: 2378–2388.
Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013; 152: 714–726.
Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011; 475: 101–105.
Schuh A, Becq J, Humphray S, Alexa A, Burns A, Clifford R et al. Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns. Blood 2012; 120: 4191–4196.
Ojha J, Secreto C, Rabe K, Ayres-Silva J, Tschumper R, Dyke DV et al. Monoclonal B-cell lymphocytosis is characterized by mutations in CLL putative driver genes and clonal heterogeneity many years before disease progression. Leukemia 2014; 28: 2395–2398.
Kumar P, Henikoff S, Ng PC . Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009; 4: 1073–1081.
Xia Y, Fan L, Wang L, Gale RP, Wang M, Tian T et al. Frequencies of SF3B1, NOTCH1, MYD88, BIRC3 and IGHV mutations and TP53 disruptions in Chinese with chronic lymphocytic leukemia: disparities with Europeans. Oncotarget 2015; 6: 5426–5434.
Sutton LA, Young E, Baliakas P, Hadzidimitriou A, Moysiadis T, Plevova K et al. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors. Haematologica 2016; 101: 959–967.
Strefford JC, Sutton LA, Baliakas P, Agathangelidis A, Malcikova J, Plevova K et al. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2. Leukemia 2013; 27: 2196–2199.
Malcikova J, Stalika E, Davis Z, Plevova K, Trbusek M, Mansouri L et al. The frequency of TP53 gene defects differs between chronic lymphocytic leukaemia subgroups harbouring distinct antigen receptors. Br J Haematol 2014; 166: 621–625.
Skowronska A, Parker A, Ahmed G, Oldreive C, Davis Z, Richards S et al. Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. J Clin Oncol 2012; 30: 4524–4532.
Sutton LA, Ljungstrom V, Mansouri L, Young E, Cortese D, Navrkalova V et al. Targeted next-generation sequencing in chronic lymphocytic leukemia: a high-throughput yet tailored approach will facilitate implementation in a clinical setting. Haematologica 2015; 100: 370–376.
Navrkalova V, Sebejova L, Zemanova J, Kminkova J, Kubesova B, Malcikova J et al. ATM mutations uniformly lead to ATM dysfunction in chronic lymphocytic leukemia: application of functional test using doxorubicin. Haematologica 2013; 98: 1124–1131.
Malcikova J, Stano-Kozubik K, Tichy B, Kantorova B, Pavlova S, Tom N et al. Detailed analysis of therapy-driven clonal evolution of TP53 mutations in chronic lymphocytic leukemia. Leukemia 2015; 29: 877–885.
Damm F, Chesnais V, Nagata Y, Yoshida K, Scourzic L, Okuno Y et al. BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders. Blood 2013; 122: 3169–3177.
Nadeu F, Delgado J, Royo C, Baumann T, Stankovic T, Pinyol M et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood 2016; 127: 2122–2130.
This study was supported by grants #2015_A09 from the Else-Kröner-Fresenius-Stiftung, #DA1787/1-1 from the Deutsche Forschungsgemeinschaft, the Lady Tata Memorial Trust (all F.D.), the Swedish Cancer Society, the Swedish Research Council, Uppsala University, Uppsala University Hospital, the Lion's Cancer Research Foundation, Uppsala, Marcus Borgström's Foundation, Uppsala, and Selander's Foundation, Uppsala, the research grants MSMT CR CEITEC2020 (LQ1601), and AZV MZCR 15-31834A/2015, H2020 ‘AEGLE, An analytics framework for integrated and personalized healthcare services in Europe’, and H2020 ‘MEDGENET, Medical Genomics and Epigenomics Network’ (No.692298), both funded by the European Commission. JCS was funded by Bloodwise (11052, 12036), the Kay Kendall Leukaemia Fund (873), Cancer Research UK (C34999/A18087, ECMC C24563/A15581), Wessex Medical Research and the Bournemouth Leukaemia Fund. This work was also supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the UK Department of Health's National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. FD is participant in the BIH-Charité Clinical Scientist Program funded by the Charité University Medical Center Berlin and the Berlin Institute of Health.
The authors declare no conflict of interest.
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Young, E., Noerenberg, D., Mansouri, L. et al. EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia. Leukemia 31, 1547–1554 (2017). https://doi.org/10.1038/leu.2016.359
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