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. 2021 May 29;11(6):986.
doi: 10.3390/diagnostics11060986.

Adverse Impact of DNA Methylation Regulatory Gene Mutations on the Prognosis of AML Patients in the 2017 ELN Favorable Risk Group, Particularly Those Defined by NPM1 Mutation

James Yu  1 , Jingxin Sun  2 , Yuan Du  3 , Rushang Patel  4 , Juan Carlos Varela  4 , Shahram Mori  4 , Chung-Che Chang  5   6
Affiliations

Adverse Impact of DNA Methylation Regulatory Gene Mutations on the Prognosis of AML Patients in the 2017 ELN Favorable Risk Group, Particularly Those Defined by NPM1 Mutation

James Yu et al. Diagnostics (Basel). .

Abstract

The 2017 ELN risk stratification has been widely adopted, but some studies have suggested the outcomes are heterogenous within the ELN risk groups and may be affected by other co-existing genetic mutations. This study evaluated the impact of DNA methylation regulatory gene (TET2, IDH1/2, DNMT3A, SETBP1) mutations (DMRGM) evaluated by NGS in the outcome of AML patients in each ELN risk group. A total of 114 patients were analyzed with a median follow-up of 12 months. Overall, 30.7% (35/114) of patients had DMRGM. DMRGM status had no impact on CR rate in each ELN risk group. The OS, however, was significantly shorter in patients with DMRGM compared to those without DMRGM (median OS: 12 vs. 33 months, p = 0.0053). Multivariate analysis showed DMRGM status was an independent unfavorable factor for OS (HR: 2.704, 95% CI: 1.451-5.041, p = 0.0017). The adverse OS impact of DMRGM was only observed in the ELN favorable group (7 months vs. not reached, p = 0.0001), but not in the intermediate or adverse group. Among the favorable group with DMRGM (n = 16), DMRGM occurred predominantly in cases with mutated NPM1 (15/16, or 93.8%). Our results suggest that DMRGM adversely impact the outcomes of ELN favorable group patients, particularly those with mutated NPM1. Further studies are warranted to confirm our observations.

Keywords: 2017 ELN risk stratification; DNA methylation regulatory gene mutations; DNMT3A; IDH1/2; NGS; TET2; acute myeloid leukemia.

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Conflict of interest statement

All authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overall survival (OS) rates by DNA methylation mutation. Red Line: DNA methylation regulatory gene (DMRGM) mutation positive. Blue Line: DMRGM negative. (A) OS rate for all AML cases by DMRGM positive versus negative (medial OS: 12 months vs. 33 months, p = 0.0053). (B) OS rate for 2017 ELN favorable group by DMRGM positive versus negative (median OS: 7 months vs. not reached, p = 0.0001). (C) OS rate for 2017 ELN intermediate group by DMRGM positive versus negative (p = 0.1172). (D) OS rate for 2017 ELN adverse group by DMRGM positive versus negative (p = 0.7773).
Figure 2
Figure 2
Overall survival (OS) rates in ELN favorable group with and without DNA-MR, ELN intermediate, and ELN adverse group. Kaplan–Meier curves for OS in ELN favorable with DMRGM (Blue line: 1, median OS: 7 months), ELN favorable without DMRGM (Red line: 2, median OS: Not reached), ELN intermediate (Green line: 3, median OS: Not reached) and ELN adverse group (Brown line: 4, median OS: 12 months). The OS of the ELN favorable with DMRGM was significantly shorter than that of the favorable group without DMRGM (p = 0.0001) or the ELN intermediate group (p = 0.0078). The median OS of ELN favorable group with DMRGM was not significantly different from that of ELN adverse group (p = 0.9937).
Figure 3
Figure 3
Mutational profile of 2017 favorable AML group in our cohort by using Circos plot model. The thickness of connection for each mutation is proportional to the number of co-occurring cases. Among 2017 favorable mutations, only NPM1 mutation significantly co-occurred with DNA methylation-related gene mutations (including DNMT3A, TET2, IDH1, and IDH2). * Abbreviation: CEBPA-Bi; Biallelic mutated CEBPA, NPM1; Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow.
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