Objective: To investigate the coexisting mutations and clinical significance of Homo sapiens neuroblastoma RAS viral oncogene homolog (NRAS) gene in acute myeloid leukemia (AML) patients.
Methods: High-throughput DNA sequencing and Sanger sequencing were used to detect 51 gene mutations. The occurrence, clinical characteristics and treatment efficacy of coexisting genes with NRAS were investigated.
Results: A total of 57 NRAS mutations (17.5%) were detected in 326 patients with AML. Compared with the patients in NRAS non-mutation group, patients in the mutant group were younger (P=0.018) and showed lower platelet count (P=0.033), but there was no significant difference in peripheral leukocyte count, hemoglobin, and sex. For FAB classification, NRAS mutation and M2 subtype showed mutually exclusive (P=0.038). Among 57 patients carried with NRAS mutation, 51 (89.5%) patients carried with other gene mutations, 25 (43.9%) carried with double gene mutations, 10 (17.5%) carried with 3 gene mutations, and 16 (28.1%) corried with ≥ 4 gene mutations. The most common coexisting gene mutation was KRAS (24.6%, 14/57), followed by FLT3-ITD (14.0%, 8/57), RUNX1 (12.3%, 7/57), NPM1 (10.5%, 6/57), PTPN11 (10.5%, 6/57), DNMT3A (10.5%, 6/57) and so on. The age (P=0.013, P=0.005) and peripheral platelet count (P=0.007, P=0.021) of patients with NPM1 or DNMT3A mutations were higher than those of the patients with wild type, but there was no significant difference in peripheral leukocyte count and hemoglobin. Also, there was no significant difference in age, peripheral leukocyte count, hemoglobin, and peripheral platelet count between the patients in KRAS, FLT3-ITD, RUNX1 or PTPN11 mutant group and the wild group. Patients with FLT3-ITD mutations showed a lower complete remission (CR) rate (P=0.044). However, there was no significant difference in CR rate between the patients with KRAS, NPM1, RUNX1, PTPN11 or DNMT3A mutations and the wild group. The CR rate of the patents with single gene mutation, double gene mutations, 3 gene mutations, and≥ 4 gene mutations were decreased gradually, and there was no significant difference in CR rate between pairwise comparisons.
Conclusion: The mutation rate of NRAS mutation is 17.5%, 89.5% of AML patients with NRAS mutation coexist with additional gene mutations. The type of coexisting mutations has a certain impact on clinical characteristics and CR rate of patients with AML.
题目: 急性髓系白血病患者中NRAS的共存基因突变分析.
目的: 探讨在成人急性髓系白血病（AML）患者中神经母细胞瘤RAS病毒致癌基因（NRAS）的共存基因突变情况及其临床意义.
方法: 采用高通量DNA测序技术联合Sanger测序法检测51种基因突变，探讨NRAS共存基因突变的发生情况、临床特征及治疗疗效.
结果: 326例AML患者中，共检测出NRAS突变57例（17.5%）。与无NRAS突变组相比，NRAS突变组患者更年轻（P=0.018），外周血小板水平更低（P=0.033），但在外周白细胞、血红蛋白、性别方面无统计学差异；FAB分型方面，NRAS突变与M2亚型互斥（P=0.038）。57例NRAS突变患者中存在51例（89.5%）共存基因突变；双基因突变25例（43.9%），3个基因突变10例（17.5%），≥4个基因突变16例（28.1%）。突变类型方面，最常见的共存基因突变为KRAS（24.6%，14/57），其他由高到低依次为FLT3-ITD（14.0%，8/57）、RUNX1（12.3%，7/57）、NPM1（10.5%，6/57）、PTPN11（10.5%，6/57）、DNMT3A（10.5%，6/57）等。NRAS伴有NPM1或DNMT3A突变患者的年龄（P=0.013，P=0.005）和外周血小板数（P=0.007，P=0.021）明显高于野生型患者，但在外周白细胞数、血红蛋白水平方面的差异无统计学意义。NRAS伴KRAS、FLT3-ITD、RUNX1或PTPN11突变组与野生型组相比，在年龄、外周白细胞数、血红蛋白、外周血小板数间的差异均无统计学意义。NRAS伴有FLT3-ITD的患者完全缓解（CR）率更低（P=0.044）。但伴KRAS、NPM1、RUNX1、PTPN11、DNMT3A突变组与野生型组之间相比，在CR率方面的差异无统计学意义。单基因突变、双基因突变、3个基因突变、≥4个基因突变患者的CR率逐次下降，两两比较，在CR率方面无统计学差异.
结论: NRAS突变发生率高达17.5%，89.5%的NRAS突变阳性的AML患者伴有额外基因突变，NRAS共存基因类型对患者的临床参数及疗效有一定影响.
Keywords: NRAS; acute myeloid leukemia; gene mutation.