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

Abstract

EGR2 mutations in CLL 5 AbstractRecurrent 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.

Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

“…CLL4 represents an ideal candidate for such an analysis, with expansive clinical and biological description [8, 12, 13, 17, 21, 24, 26, 29, 31-33, 40, 41] and protracted clinical follow-up. Our study confirms previous studies incorporating samples from this patient cohort showing the impact of TP53ab on PFS and OS in MVA, SF3B1, EGR2 [25,26], RPS15 [1,24] and NFKBIE [25,28,42] mutations on OS in univariate analysis, with SF3B1 and EGR2 mutations retained as independent markers of OS in MVA.…”

“…The trial demonstrated superior response rates and progression-free survival (PFS) for FC-treated patients compared with those patients treated with FDR or CHL. Previous genomic analysis of this trial has shown TP53 [8], SF3B1 [17], NOTCH1 (coding [17] and non-coding [21]), ATM plus del(11q) [12] and EGR2 [26] lesions to have prognostic significance in multivariate analysis (MVA) and of RPS15 [24] in univariate analysis. The importance of data from CLL4 may be questioned given the studies showing the superior efficacy of FC plus an anti-CD20 antibody (FCR) compared with chemotherapy alone, with the exception of patients with a NOTCH1 mutation [20], and emerging data suggesting the superiority of novel agents compared with chemotherapy-based regimens.…”

“…In particular, next generation sequencing of large patient cohorts has led to the discovery of These authors contributed equally: Anna Schuh, Jonathan C. Strefford recurring genomic mutations that cluster into distinct biological signalling pathways. Mutations of specific genes including TP53 [4][5][6][7][8][9][10], ATM [9,[11][12][13][14], BIRC3 [9,15,16], SF3B1 [9,[17][18][19][20], NOTCH1 [1,9,15,17,[20][21][22][23], RPS15 [2,24], EGR2 [25,26] and KRAS [27,28] are associated with poorer outcome, especially shorter time to first treatment or overall survival (OS). However, numerous factors influence the clinical significance of a driver mutation in an individual patient.…”

Developing an Integrated Genomic Profile for Cancer Patients with the Use of NGS Data

“…This division between groups was used to perform the inter-group comparisons and the classification for the predictive analysis. The separation for the predictive analysis was made based on the assumption that, for the RNAseq analysis, patients with mutated EGR2 gene have a good prognosis [26] and, for the WES analysis, the patients with unmutated the IGVH gene are characterized as stable [27].…”

An update on: molecular genetics of high-risk chronic lymphocytic leukemia

“…Several molecular studies have identified a set of genes, including NOTCH1, SF3B1 BIRC3, RSP15, and EGR2, as novel molecular biomarkers that account, at least in part, for chemorefractoriness in addition to TP53 disruption. These genetic aberrations appear to be mutually exclusive with disruption of TP53, at least in most cases, indicating that multiple alternative pathways can lead to CIT failure [11,[20][21][22][23]. In particular, in the case of FCR, mutations of BIRC3 (Baculoviral IAP Repeat Containing 3) stand out as a novel predictor of treatment failure.…”