CLL patients harboring EGR-2 mutations represent a so far undefined sub-group of CLL patients with a very poor outcome
On 3rd January 2017, E. Young from the Science for Life Laboratory of the Uppsala University, Sweden, and colleagues published data in Leukemia regarding the prognostic impact of EGR2 mutations in patients with CLL. Mutations in EGR2 were looked for in 2,403 CLL patients.
- Overall prevalence of EGR2 mutations = 91/2,403 (3.8%) investigated cases
- Compared with wild-type, patients with mutated EGR2 were significantly:
- Younger (57 vs 62 years; P = 0.0042)
- More likely to have an advanced Binet stage at diagnosis (Binet B/C 56 vs 30%; P = 0.0005)
- More likely to express wild-type IGHV genes (81 vs 61%; P = 0.0041) and del(11)(q22) (33 vs 18%; P = 0.0161)
- More likely to express higher levels of CD38 (67 vs 27%; P = 0.0001)
- Targeted deep-sequencing in EGR2-mutated patients (n = 38):
- Patients with EGR2 mutations also frequently had SF3B1 mutations (4/38; 10.5%), TP53 mutations (7/38; 18.4%), and ATM lesions (12/38; 31.6%),
- Seven patients harbored aberrations NOTCH signalling genes (18.4%): FBXW7 (n=3), NOTCH1 (n=3), SPEN (n=1)
- Screening cohort (n = 1,178 cases with available data):
- EGR2-mutated patients had significantly worse median Time To First Treatment (TTFT; 7.8 vs 5 months; HR 1.86; 95% CI, 1.35–2.57; P < 0.001)
- EGR-2 mutated patients had significantly worse median OS (4.7 vs 2 months; HR 2.03; 95% CI, 1.41–2.92; P < 0.001)
- In multivariate analysis, EGR2 mutation was an independent negative prognostic marker for TTFT (HR 1.44; 95% CI, 1.01–2.06; P = 0.047) and OS (HR 1.72; 95% CI, 1.12–2.65; P = 0.014)
- Validation cohorts:
- UK CLL4 trial validation cohort (n = 366); multivariate analysis confirmed EGR2 mutation status as an independent risk factor for OS (HR 1.95; 95% CI, 1.02–3.73; P = 0.043)
- CLL Research Consortium validation cohort (n = 486 cases with available data); multivariate analysis confirmed EGR2 as an independent risk factor for TTFT (HR 1.92; 95% CI, 1.11–3.32; P = 0.020), although only borderline significance was reported for OS (HR 1.90; 95% CI, 0.88–4.12; P = 0.10)
The authors concluded that patients harboring EGR-2 mutations represent a so far undefined sub-group of CLL patients with a very poor outcome. In their screening cohort, survival analysis found EGR2 mutations significantly predicted a negative prognosis (short TTFT and OS), similar to CLL patients with aberrant TP53. Lastly, this negative, prognostic impact of mutations in the EGR2 gene was also observed in aggressive subgroups, in especially in U-CLL and TP53 patients who displayed particularly short OS.
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. Leukemia advance online publication, 3 January 2017; doi:10.1038/leu.2016.359.