TET2合并DNMT3A突变及其他共存基因突变对急性髓系白血病患者预后的影响

Prognostic impact of TET2 mutation combined with DNMT3A mutation or other concomitant mutations in acute myeloid leukemia

    摘要
  • 摘要:
      目的  探究TET2合并DNMT3A突变及其他共存基因突变对成人非M3型急性髓系白血病（acute myeloid leukemia，AML）患者预后的影响。
      方法  回顾性分析2018年1月至2021年9月于南昌大学第一附属医院确诊的初治且行血液肿瘤相关突变基因外显子二代测序检测的512例成人 AML（非 M3 型）患者的临床资料，分析患者的临床特征、疗效及生存情况。
      结果  本研究共纳入110例AML患者，TET2突变组64例，DNMT3A单突变组46例。男性50例（45.5%），中位年龄54（15～79）岁。TET2基因突变频率为12.5%（64/512），98.4%（63/64）患者突变基因数≥2个，每例患者平均合并5.2个突变基因。NPM1（43.8%）、DNMT3A（42.2%）、FLT3-ITD/TKD（40.6%）、CEBPA（26.6%）、TTN（20.3%）为TET2突变常见的共存突变基因。TET2合并DNMT3A突变患者初次诱导完全缓解（complete response，CR）率为46.2%，略低于TET2单突变患者的76.9%（P=0.077），与DNMT3A单突变患者无显著性差异（P=0.952）。TET2合并DNMT3A突变患者的中位总生存（median overall survival，mOS）时间为9.5个月，明显低于TET2单突变患者（P=0.002），而与DNMT3A单突变患者无显著性差异（P=0.414）。三者的中位无复发生存（median relapse- free survival，mRFS）时间无显著性差异（P>0.05）。在TET2突变背景下，合并K/NRAS突变患者的CR率为28.6%，明显低于无K/NRAS突变患者的75.0%（P=0.030），合并FLT3-ITD突变患者的mOS明显短于无FLT3-ITD突变患者（P=0.030）。多因素分析显示年龄≥60岁、合并FLT3-ITD突变、初次诱导未达CR是影响TET2突变AML患者总生存时间（overall survival，OS）的独立危险因素，DNMT3A突变不影响TET2突变患者OS。
      结论  TET2突变是AML患者常见突变，且常合并共存基因突变。共存基因突变与TET2突变共同影响AML患者预后。基于二代测序的基因突变检测对指导AML精确分层及精准治疗具有重要意义。

     

    Abstract:
      Objective  To determine the prognostic significance of a ten-eleven translocation-2 (TET2) mutation combined with a DNA methyltransferases 3A (DNMT3A) mutation or other concomitant mutations in patients with acute myeloid leukemia (AML) (non-M3).
      Methods  A total of 512 newly diagnosed AML (non-M3) patients who underwent next-generation sequencing of hematologic tumor-associated mutated gene exons were analyzed. Patient clinical characteristics, treatment efficacy, and patient survival were also analyzed.
      Results  A total of 110 patients were enrolled in this study. Sixty-four patients with TET2 mutations were selected as the research group, and 46 patients carrying single mutations in DNMT3A were included as a control group. The study included 50 males (45.5%) with a median age of 54 years (15-79 years). A single TET2 mutation was detected in 12.5% (64/512) of AML patients; 98.4% (63/64) of patients carried more than 2 mutated genes, with each patient having an average of 5.2 mutated genes. NPM1 (43.8%), DNMT3A (42.2%), FLT3-ITD/TKD (40.6%), CEBPA (26.6%), TTN (20.3%) were the genes most frequently co-mutated with TET2. The complete response (CR) rate of patients with TET2 and DNMT3A mutations was 46.2%, lower than that of patients with a TET2 mutation only (P=0.077), but not significantly different from that of patients with DNMT3A mutation only (P=0.952). The median overall survival (mOS) time of patients with TET2 and DNMT3A mutations was 9.5 months, significantly lower than that of patients with TET2 mutation only (P=0.002). No significant difference was detected in median relapse-free survival (mRFS) time among the three groups (P>0.05). In the context of a TET2 mutation, the CR rate of patients with a K/NRAS mutation was significantly lower than that of patients without a K/NRAS mutation (28.6% vs. 75.0%, P=0.030), and the mOS of patients with an FLT3-ITD mutation was significantly shorter than that of patients without an FLT3-ITD mutation (P=0.030). Multivariate analysis showed that age≥60 years, concomitant FLT3-ITD mutation, and failure to reach CR during induction therapy were independent risk factors for OS in AML patients carrying TET2 mutations, while DNMT3A mutations had no effect on OS in patients with TET2 mutations.
      Conclusions  TET2 mutations are common in AML patients and often accompanied by concomitant gene mutations. TET2 mutations and concomitant mutations affect AML patient prognosis. Gene mutation detection based on next-generation sequencing is of great significance for accurate stratification and precise treatment of AML patients.

     

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