Mutational spectrum of acute myeloid leukemia patients with double CEBPA mutations based on next-generation sequencing and its prognostic significance

Abstract

The aim of this study was to profile the spectrum of genetic mutations in acute myeloid leukemia (AML) patients co-occurring with CEBPA double mutation (CEBPAdm). Between January 1, 2012, and June 30, 2017, 553 consecutive patients with de novo AML were screened for CEBPA mutations. Out of these, 81 patients classified as CEBPAdm were analyzed further by a sensitive next-generation sequencing assay for mutations in 112 candidate genes. Within the CEBPA gene itself, we found 164 mutations. The most common mutated sites were c.936_937insGAG (n = 11/164, 6.71%) and c.939_940insAAG (n = 11/164, 6.71%), followed by c.68dupC (n = 10/164, 6.10%). The most common co-occurring mutations were found in the CSF3R (n = 16/81, 19.75%), WT1 (n = 15/81, 18.52%), and GATA2 (n = 13/81, 16.05%) genes. Patients with CSF3R mutations had an inferior four-year relapse-free survival (RFS) than those with the wild-type gene (15.3% versus 46.8%, respectively; P = 0.021). Patients with WT1 mutations had an inferior five-year RFS compared with those without such mutations (0% versus 26.6%, respectively, P = 0.003). However, GATA2, CSF3R, WT1 mutations had no significant influence on the overall survival. There were some differences in the location of mutational hotspots within the CEBPA gene, as well as hotspots of other co-occurring genetic mutations, between AML patients from Chinese and Caucasian populations. Some co-occurring mutations may be potential candidates for refining the prognoses of AML patients with CEBPAdm in the Chinese population.

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

“…Multiple mechanisms for CEBPA inhibition have been identified in leukemic cells, from genetic to epigenetic, from transcriptional to translational and post-translational levels (Table 3, Figure 3). Mutations of CEBPA are also associated with mutations in TET2, the most frequently co-mutated gene (34%), followed by GATA2 (21%), WT1 (13%), DNMT3A (9%) and ASXL1 (9%) [130][131][132][133]. Recently, a direct co-occurrence between CEBPA and granulocyte colony-stimulating factor receptor (CSF3R) mutations has been reported [134,135].…”

Clonal Evolution of Acute Myeloid Leukemia with CEBPA Double Mutations after Long-Term Remission: Case Report and a Literature Review

“…Mutations in the CEBPA gene occur in 7%-15% of all acute myeloid leukemia (AML) patients [1,2]. However, we found that the frequency of such mutation may be high in Chinese AML patients [3,4]. Although AML with CEBPA double mutations (CEBPA dm ) indicates a favorable outcome, recent data show that more than 50% of patients finally relapsed when consolidated with chemotherapy alone [5].…”

“…Just before transplantation, no risk factors except for the mild hepatic dysfunction and age were found, the hematopoietic cell transplantation-comorbidity index (HCT-CI) was 1, and the age-adjusted HCT-CI score was 2 [4,5]. Meanwhile, bone marrow examination revealed active disease with 6.7% myeloblasts.…”

High CXCR2 expression predicts poor prognosis in adult patients with acute myeloid leukemia

“…For example, in AML with CEBPA double mutations, a low-risk group, some patients experience continuous remission, while others relapse after cycles of consolidation chemotherapy or stem cell transplantation. 5 , 6 Studies from different medical centers have attempted to explore new markers for re-stratifying these patients. 7 , 8 Therefore, there is an urgent need to uncover potential markers for AML stratification.…”