Περίληψη:
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. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Συγγραφείς:
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.
Damm, F.
Λέξεις-κλειδιά:
ATM protein; biological marker; CD38 antigen; early growth response factor 2; Notch1 receptor; protein p53; early growth response factor 2; EGR2 protein, human, adult; advanced cancer; aged; antigen expression; Article; cancer patient; cancer prognosis; cancer screening; cancer survival; chronic lymphatic leukemia; female; gene frequency; gene mutation; groups by age; human; major clinical study; male; mutational analysis; overall survival; priority journal; prognostic assessment; sequence analysis; time to treatment; classification; genetics; Leukemia, Lymphocytic, Chronic, B-Cell; middle aged; mortality; mutation; proportional hazards model; tumor suppressor gene, Adult; Aged; Early Growth Response Protein 2; Female; Genes, p53; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Proportional Hazards Models
