Elghannam Doaa M, Abousamra Nashwa Khayrat, Shahin Doaa A, Goda Enas F, Azzam Hanan, Azmy Emad, El-Din Manal Salah, El-Refaei Mohamed F
Department of Clinical Pathology, Hematology Unit, Faculty of Medicine, Mansoura University, USA.
Egypt J Immunol. 2009;16(1):9-15.
The pathogenesis of acute myeloid leukemia (AML) involves the cooperation of mutations promoting proliferation/survival and those impairing differentiation. Point mutations of the N-RAS gene are the most frequent somatic mutations causing aberrant signal-transduction in acute myeloid leukemia (AML). The aim of the present work is to study the frequency and prognostic significance of N-RAS gene mutations (N-RASmut) in de novo Egyptian adult AML. Bone marrow specimens from 150 patients with de novo acute myeloid leukemia and controls were analyzed by genomic PCR-SSCP at codons 12, 13 (exon 1), and 61 (exon 2) for N-RAS mutations. In 12.7% (19/150) AML cases, N-RAS gene mutations were found and were observed more frequently in the FAB subtype M4eo (P = 0.028) and with codon 12, 13 (14 of 19; 73.7%). Patients with N-RAS mutation had a significant lower peripheral and marrow blasts (P = 0.004, P = 0.03) and clinical outcome did not improve more than in patients without mutation. In patients with N-RAS gene mutation vs. those without, complete remission rate was (63.2% vs. 56.5%; P = 0.46), resistant disease (15.8% vs. 23.6%; P = 0.51), three years overall survival (44% vs 42%; P= 0.85) and disease free survival (42.1% vs. 38.9%, P = 0.74). Multivariate analysis showed that age was the strongest unfavorable factor for overall survival (relative risk [RR], 1.9; P = 0.002), followed by cytogenetics (P = 0.004). FAB types, N-RAS mutation and leukocytosis were the least important. In conclusion, the frequency and spectrum of N-RAS gene mutation differ between biologically distinct subtypes of AML but do not significantly influence prognosis and clinical outcome in patients with AML.
急性髓系白血病（AML）的发病机制涉及促进增殖/存活的突变与损害分化的突变之间的协同作用。N-RAS基因的点突变是急性髓系白血病（AML）中导致异常信号转导的最常见体细胞突变。本研究的目的是探讨埃及成年初治AML患者中N-RAS基因突变（N-RASmut）的频率及其预后意义。采用基因组PCR-SSCP技术，对150例初治急性髓系白血病患者及对照者骨髓标本的N-RAS基因第12、13密码子（第1外显子）和第61密码子（第2外显子）进行突变分析。在12.7%（19/150）的AML病例中发现了N-RAS基因突变，在FAB亚型M4eo中更常见（P = 0.028），且第12、13密码子突变者居多（19例中有14例；73.7%）。N-RAS基因突变患者的外周血和骨髓原始细胞显著减少（P = 0.004，P = 0.03），临床结局改善程度并不优于未突变患者。N-RAS基因突变患者与未突变患者相比，完全缓解率分别为（63.2%对56.5%；P = 0.46），耐药率分别为（15.8%对23.6%；P = 0.51），三年总生存率分别为（44%对42%；P = 0.85），无病生存率分别为（42.1%对38.9%，P = 0.74）。多因素分析显示，年龄是总生存的最强不利因素（相对危险度[RR]，1.9；P = 0.002），其次是细胞遗传学（P = 0.004）。FAB类型、N-RAS突变和白细胞增多症的影响最小。总之，AML不同生物学亚型中N-RAS基因突变的频率和谱不同，但对AML患者的预后和临床结局无显著影响。
