Abstract：
OBJECTIVE: To investigate the molecular characteristics and clinical prognosis of the neuroblastoma RAS viral oncogene (NRAS) in patients with primary cytogenetically normal acute myeloid leukemia (AML).
METHODS: A total of 171 adult patients with cytogenetically normal primary AML were collected, and 34 gene mutations in these patients were detected by targeted next-generation sequencing.
RESULTS: Among 171 patients with cytogenetically normal AML(CN-AML), 17 (9.9%) patients had found NRAS mutations. Among the 17 NRAS mutant patients, 16 cases were associated with the concomitant gene, and NRAS mutation (NRASmut) was significantly positively correlated with DNMT3A mutation (DNMT3Amut) (P=0.011) and KRAS mutation (P=0.008) compared with the NRAS wild-type (NRASwt) group. The frequency of NRASmutDNMT3Amut clone was significantly higher in CN-AML patients with NRAS mutation (8/17, 47%). The total NRASmut group showed no significant differences on clinical characteristics, CR rate after induction therapy, OS, and RFS as compared with NRASwt group. However, patients with NRASmutDNMT3Amut provided a shorter effect on OS (median:7 vs 15 months; P=0.036) and RFS (median: 3 vs 12 months; P=0.003) than those with NRASwt, though no statistic differences on demographics, lab parameters, treatment and CR rate of patients receiving induction therapy. Multivariate analysis showed that NRASmutDNMT3Amut subtype could independently affect the RFS of CN-AML patients (HR:3.210, 95%CI:1.078-9.557, P=0.036).
CONCLUSIONS: NRASmutDNMT3Amut clones have a high frequency of occurrence and show a poor survival prognosis. Our findings highlight potentially novel aspects of the underlying biology of NRASmutDNMT3Amut commutation in adult de novo CN-AML.
METHODS: A total of 171 adult patients with cytogenetically normal primary AML were collected, and 34 gene mutations in these patients were detected by targeted next-generation sequencing.
RESULTS: Among 171 patients with cytogenetically normal AML(CN-AML), 17 (9.9%) patients had found NRAS mutations. Among the 17 NRAS mutant patients, 16 cases were associated with the concomitant gene, and NRAS mutation (NRASmut) was significantly positively correlated with DNMT3A mutation (DNMT3Amut) (P=0.011) and KRAS mutation (P=0.008) compared with the NRAS wild-type (NRASwt) group. The frequency of NRASmutDNMT3Amut clone was significantly higher in CN-AML patients with NRAS mutation (8/17, 47%). The total NRASmut group showed no significant differences on clinical characteristics, CR rate after induction therapy, OS, and RFS as compared with NRASwt group. However, patients with NRASmutDNMT3Amut provided a shorter effect on OS (median:7 vs 15 months; P=0.036) and RFS (median: 3 vs 12 months; P=0.003) than those with NRASwt, though no statistic differences on demographics, lab parameters, treatment and CR rate of patients receiving induction therapy. Multivariate analysis showed that NRASmutDNMT3Amut subtype could independently affect the RFS of CN-AML patients (HR:3.210, 95%CI:1.078-9.557, P=0.036).
CONCLUSIONS: NRASmutDNMT3Amut clones have a high frequency of occurrence and show a poor survival prognosis. Our findings highlight potentially novel aspects of the underlying biology of NRASmutDNMT3Amut commutation in adult de novo CN-AML.
摘要：
目的：探讨原发性细胞遗传学正常急性髓系白血病(AML)患者神经母细胞瘤RAS病毒癌基因(NRAS)的分子特征及临床预后。
方法：收集171例细胞遗传学正常的成人原发性AML患者，通过靶向下一代测序检测到这些患者的34个基因突变。
结果：在171例细胞遗传学正常AML（CN-AML）患者中，17例（9.9％）患者发现NRAS突变。在17名NRAS突变患者中，16例伴随基因，与NRAS野生型(NRASwt)组相比,NRAS突变(NRASmut)与DNMT3A突变(DNMT3Amut)(P=0.011)和KRAS突变(P=0.008)呈显著正相关。在具有NRAS突变的CN-AML患者中，NRASmutDNMT3Amut克隆的频率显着升高（8/17，47％）。总NRASmut组在临床特征上没有显着差异，诱导治疗后的CR率，操作系统,和RFS与NRASwt组比较。然而,NRASmutDNMT3Amut患者对OS（中位数：7vs15个月；P=0.036）和RFS（中位数：3vs12个月；P=0.003）的影响比NRASwt患者更短，尽管人口统计学上没有统计差异，实验室参数,接受诱导治疗的患者的治疗和CR率。多因素分析显示，NRASmutDNMT3Amut亚型可独立影响CN-AML患者的RFS（HR：3.210，95CI：1.078-9.557，P=0.036）。
结论：NRASmutDNMT3Amut克隆发生频率高，生存预后差。我们的发现强调了成人从头CN-AML中NRASmutDNMT3Amut换向的潜在生物学方面。
方法：收集171例细胞遗传学正常的成人原发性AML患者，通过靶向下一代测序检测到这些患者的34个基因突变。
结果：在171例细胞遗传学正常AML（CN-AML）患者中，17例（9.9％）患者发现NRAS突变。在17名NRAS突变患者中，16例伴随基因，与NRAS野生型(NRASwt)组相比,NRAS突变(NRASmut)与DNMT3A突变(DNMT3Amut)(P=0.011)和KRAS突变(P=0.008)呈显著正相关。在具有NRAS突变的CN-AML患者中，NRASmutDNMT3Amut克隆的频率显着升高（8/17，47％）。总NRASmut组在临床特征上没有显着差异，诱导治疗后的CR率，操作系统,和RFS与NRASwt组比较。然而,NRASmutDNMT3Amut患者对OS（中位数：7vs15个月；P=0.036）和RFS（中位数：3vs12个月；P=0.003）的影响比NRASwt患者更短，尽管人口统计学上没有统计差异，实验室参数,接受诱导治疗的患者的治疗和CR率。多因素分析显示，NRASmutDNMT3Amut亚型可独立影响CN-AML患者的RFS（HR：3.210，95CI：1.078-9.557，P=0.036）。
结论：NRASmutDNMT3Amut克隆发生频率高，生存预后差。我们的发现强调了成人从头CN-AML中NRASmutDNMT3Amut换向的潜在生物学方面。
