Prognostic impact of DNMT3A mutations in patients with intermediate cytogenetic risk profile acute myeloid leukemia
Prognostic impact of DNMT3A mutations in patients with intermediate cytogenetic risk profile acute myeloid leukemia
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DOI：
10.1111/j.1600-0609.2011.01716.x
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发表时间：
2012-02-01
影响因子：
3.1
通讯作者：
Schwarz, Jiri
中科院分区：
文献类型：
--
作者：
Markova, Jana;Michkova, Petra;Schwarz, Jiri
目的：最近，大约 25% 的急性髓系白血病 (AML) 病例中发现了 DNMT3A 基因突变，尤其是单核细胞 AML。研究发现，它们可以预测突变患者的总生存期 (OS) 较差。患者和方法：使用 RT-PCR 和直接测序来检测 226 名具有中危 (IR) 细胞遗传学的 AML 患者是否存在 DNMT3A 突变。结果：226 名患者中有 67 名 (29.6%) 携带 DNMT3A 基因突变。 DNMT3A 突变的发生与女性 (P = 0.027) 和 FLT3/ITD (P = 0.003) 的存在相关，但与特定的 FAB 亚型无关。 DNMT3A 突变患者的初始白细胞计数高于无突变患者 (P = 0.064)，只是因为这些病例中 FLT3/ITD 的发生率较高。突变组和野生型组在达到完全缓解 (CR) 方面没有差异 (P = 0.380)。 OS 不受 DNMT3A 突变的影响（P = 0.251），但在 DNMT3A 阴性病例中达到 CR 的患者 OS 更长（P = 0.025）。 DNMT3A突变患者的复发率较高（P = 0.007）。同时携带 DNMT3A 突变和 FLT3/ITD 的患者比携带单一 DNMT3A 突变的患者 (P = 0.044) 或仅携带 FLT3/ITD 的患者 (P = 0.058) 更容易复发。即使在 FLT3/ITD 阴性组中，DNMT3A 突变也与较高的复发率相关（P = 0.072）。达到 CR 后，多变量分析表明这两个遗传因素是复发的独立预测因子（P < 0.001）。 30名双突变（FLT3/ITD+、DNMT3A+）患者中只有3人还活着，他们都接受了造血干细胞移植。结论：我们通过IR细胞遗传学证实了AML患者DNMT3A突变的高发生率。当仅分析达到 CR 的患者时，具有 DNMT3A 突变的患者复发率更高且 OS 较差。双突变患者的预后非常差。
Objectives: Recently, mutations in DNMT3A gene have been described in about 25% acute myeloid leukemia (AML) cases, preferentially in monocytic AML. They were found to predict worse overall survival (OS) of mutated patients. Patients and methods: RT-PCR followed by direct sequencing was used to test the presence of DNMT3A mutations in 226 AML patients with an intermediate-risk (IR) cytogenetics. Results: Sixty-seven patients of 226 (29.6%) carried a mutation in the DNMT3A gene. Occurrence of DNMT3A mutations was associated with female sex (P = 0.027) and with the presence of FLT3/ITD (P = 0.003), but not with particular FAB subtypes. Patients with DNMT3A mutation had higher initial WBC counts than those without it (P = 0.064) only because of higher incidence of FLT3/ITD within these cases. There was no difference between mutated and wild-type groups in reaching complete remission (CR) (P = 0.380). OS was not affected by DNMT3A mutation (P = 0.251), but OS of patients who reached CR was longer in DNMT3A negative cases (P = 0.025). Patients with DNMT3A mutation had a higher relapse rate (P = 0.007). Patients carrying both the DNMT3A mutation and FLT3/ITD relapsed more often than either patients with single DNMT3A mutation (P = 0.044) or patients with FLT3/ITD only (P = 0.058). DNMT3A mutations were associated with higher relapse rate even within the FLT3/ITD-negative group (P = 0.072). After reaching CR, these two genetic factors were independent predictors of relapse at multivariate analysis (P < 0.001). Only three of 30 double-mutated (FLT3/ITD+, DNMT3A+) patients are still alive, all of them having undergone hematopoietic stem cell transplant. Conclusions: We have confirmed the high incidence of DNMT3A mutations in patients with AML with IR cytogenetics. Patients with DNMT3A mutations relapse more often and have inferior OS when only patients achieving CR are analyzed. Double-mutated patients have a very poor prognosis.