Persistent DNMT3A mutation burden in DNMT3A mutated adult cytogenetically normal acute myeloid leukemia patients in long-term remission
Persistent DNMT3A mutation burden in DNMT3A mutated adult cytogenetically normal acute myeloid leukemia patients in long-term remission
复制标题
长期缓解的 DNMT3A 突变成人细胞遗传学正常急性髓系白血病患者的持续 DNMT3A 突变负担
DOI：
10.1016/j.leukres.2016.09.001
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发表时间：
2016-10-01
影响因子：
2.7
通讯作者：
Xu, Yang
中科院分区：
文献类型：
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作者：
Sun, Yanjun;Shen, Hongjie;Xu, Yang
DNMT 3A突变在细胞遗传学正常的急性髓性白血病（CN-AML）患者中很常见，并且可以在疾病发生前多年存在。然而，CN-AML中DNMT 3A突变负荷的临床意义仍不清楚。在这项研究中，81例DNMT 3A突变的成人CN-AML患者在2005年3月至2015年5月期间首次完全缓解（CR）。所有患者均被鉴定为具有DNMT 3A外显子23突变，并且R882 H是最常见的变体（n=49，60.49%）。共发现48例患者（48/81，59.3%）在达到CR后存在DNMT 3A突变。在最终随访检查时，40例患者仍处于CR状态，其中8例（8/81，9.9%）发现仍有DNMT 3A突变。对不同疾病状态下NPM 1、FLT 3-ITD和DNMT 3A突变顺序的分析显示，DNMT 3A可能是白血病细胞中最早的突变。此外，我们使用新一代测序技术确定了12例新发和2例复发样本中可能的基因畸变。NPM 1（5/12，41.7%）、FLT 3-ITD（5/12，41.7%）和CEBPA突变（4/12，33.3%）是最常见的共存突变。在复发样本中，可以观察到额外的基因畸变，其中一些在AML患者中从未报告过。81例DNMT 3A突变的CN-AML患者的2年总生存率（2-OS）为39.0%。首次CR时DNMT 3A突变阴性（n = 33）和阳性（n = 48）患者的2-OS（38.2% vs 41.6%，P =0.2256）和2年无病生存期（2-DFS：28.5% vs 34.3%，P = 0.1831）无差异。总之，我们的研究结果表明，DNMT 3A突变负荷可以在长期缓解的成年DNMT 3A突变CN-AML患者中持续存在，并且DNMT 3A突变是白血病细胞发展的早期事件。(C)2016爱思唯尔有限公司版权所有
DNMT3A mutations are frequent in cytogenetically normal acute myeloid leukemia (CN-AML) patients and can be present many years before the disease develops. However, the clinical significance of DNMT3A mutation burden in CN-AML remains unclear. In this study, 81 DNMT3A mutated adult CN-AML patients in their first complete remission (CR) were enrolled at our center from March 2005 to May 2015. All patients were identified as having DNMT3A exon 23 mutations, and R882H was the most frequent variant (n=49, 60.49%). A total of 48 patients (48/81, 59.3%) were found to have DNMT3A mutations upon achieving CR. At the final follow-up exam, 40 patients remained in CR, 8 of which (8/81, 9.9%) were found to still have DNMT3A mutations. Analysis of the order of NPM1, FLT3-ITD and DNMT3A mutations for different disease statuses revealed that DNMT3A might be the earliest mutation in leukemic cells. In addition, we determined the possible gene aberrations in 12 de novo and 2 relapsed samples using next generation sequencing. NPM1 (5/12, 41.7%), FLT3-ITD (5/12, 41.7%) and CEBPA mutations (4/12, 33.3%) were the most frequent coexisting mutations. In the relapsed samples, additional genes aberrations could be observed, and some of them were never reported in AML patients. The 2-year overall survival (2-OS) for 81 DNMT3A mutated CN-AML patients was 39.0%. No differences was found in 2-OS (38.2% vs 41.6%, P=0.2256) and 2-year disease free survival (2-DFS: 28.5% vs 34.3%, P = 0.1831) between patients with negative (n = 33) and positive DNMT3A mutation findings (n = 48) at the first CR. In summary, our findings indicated that DNMT3A mutation burden could persist in adult DNMT3A mutated CN-AML patients in long-term remission and that DNMT3A mutation was the early event in the development of leukemic cells. (C) 2016 Elsevier Ltd. All rights reserved.