Li Weijing, Cui Lei, Gao Chao, Liu Shuguang, Zhao Xiaoxi, Zhang Ruidong, Zheng Huyong, Wu Minyuan, Li Zhigang
Hematology & Oncology Laboratory, Beijing Pediatric Research Institute Beijing Key Laboratory of Pediatric Hematology Oncology Key Laboratory of Major Diseases in Children National Key Discipline of Pediatrics, Ministry of Education Hematology & Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Medicine (Baltimore). 2017 Aug;96(31):e7620. doi: 10.1097/MD.0000000000007620.
DNA methyltransferase 3A (DNMT3A) mutations have been found in approximately 20% of adult acute myeloid leukemia (AML) patients and in 0% to 1.4% of children with AML, and the hotspots of mutations are mainly located in the catalytic methyltransferase domain, hereinto, mutation R882 accounts for 60%. Although the negative effect of DNMT3A on treatment outcome is well known, the prognostic significance of other DNMT3A mutations in AML is still unclear. Here, we tried to determine the incidence and prognostic significance of DNMT3A mutations in a large cohort in Chinese childhood AML.
We detected the mutations in DNMT3A exon 23 by polymerase chain reaction and direct sequencing in 342 children with AML (0-16 years old) from January 2005 to June 2013, treated on BCH-2003 AML protocol. The correlation of DNMT3A mutations with clinical characteristics, fusion genes, other molecular anomalies (FLT3 internal tandem duplication [FLT3-ITD], Nucleophosmin 1, C-KIT (KIT proto-oncogene receptor tyrosine kinase), and Wilms tumor 1 mutations), and treatment outcome were analyzed.
DNMT3A mutations were detected in 4 out of 342 (1.2%) patients. Two patients were PML-RARA positive and 1 patient was FLT3-ITD positive. The mutations in coding sequences included S892S, V912A, R885G, and Q886R. Furthermore, there was 1 intronic mutation (c.2739+55A>C) found in 1 patient. No association of DNMT3A mutations with common clinical features was found. Two patients with DNMT3A mutations died of relapse or complications during treatment. One patient gave up treatment due to remission induction failure in day 33. Only 1 patient achieved continuous complete remission.
DNMT3A mutations were rare in Chinese children with AML including PML-RARA positive APL. The mutation positions were different from the hotspots reported in adult AML. DNMT3A mutations may have adverse impact on prognosis of children with AML.
在大约20%的成年急性髓系白血病（AML）患者中发现了DNA甲基转移酶3A（DNMT3A）突变，而在儿童AML患者中的突变率为0%至1.4%，且突变热点主要位于催化甲基转移酶结构域，其中R882突变占60%。尽管DNMT3A对治疗结果的负面影响已为人所知，但其他DNMT3A突变在AML中的预后意义仍不清楚。在此，我们试图确定中国儿童AML大样本队列中DNMT3A突变的发生率及其预后意义。
我们采用聚合酶链反应和直接测序法，检测了2005年1月至2013年6月期间按照BCH - 2003 AML方案治疗的342例0至16岁AML儿童患者的DNMT3A外显子23突变情况。分析了DNMT3A突变与临床特征、融合基因、其他分子异常（FLT3内部串联重复[FLT3 - ITD]、核仁磷酸蛋白1、C - KIT（KIT原癌基因受体酪氨酸激酶）和威尔姆斯瘤1突变）以及治疗结果之间的相关性。
342例患者中有4例（1.2%）检测到DNMT3A突变。2例患者PML - RARA阳性，1例患者FLT3 - ITD阳性。编码序列中的突变包括S892S、V912A、R885G和Q886R。此外，在1例患者中发现了1个内含子突变（c.2739 + 55A>C）。未发现DNMT3A突变与常见临床特征之间存在关联。2例DNMT3A突变患者在治疗期间死于复发或并发症。1例患者因第33天诱导缓解失败而放弃治疗。仅1例患者实现持续完全缓解。
DNMT3A突变在中国儿童AML（包括PML - RARA阳性的急性早幼粒细胞白血病）中较为罕见。突变位置与成人AML中报道的热点不同。DNMT3A突变可能对儿童AML的预后产生不利影响。
