摘要：
Objective To evaluate the prevalence and distribution of C-kit,NPM1 and FLT3 gene mutations in patients with acute myeloid leukemia (AML),and to analyze the relationship between the gene mutations and their prognosis.Methods Mutations in exon 8 and 17 of C-kit gene,exon 12 of NPM1 gene,exon 20 of FLT3-TKD gene,and exon 14/15 of FLT3-ITD gene were detected by direct sequencing.Clinical data was collected and followed up if the patient had accepted treatment in our hospital.Results Among the 656 AML patients,mutations in C-kit exon 8 were found in 6 patients (0.9％),C-kit exon 17 in 33(5.0％),NPM1 in 169 (25.8％),FLT3-TKD in46 (7.1％),and FLT3-ITD in 178 (27.1％).Six subtypes of mutations were detected in C-kit exon 8,8 in C-kit exon 17,11 in FLT3-TKD,15 in NPM1,of which 5 were not reported before.C-kit exon 17 mutations were more frequently detected in patients with t(8;21) and exon 8 in patients with inv(16) cytogenetic abnormality.No other gene mutations except FLT3 were detected in M3 patients.NPM1 and ITD mutations were often detected in individuals with normal cytogenetics or M5 and M1 of FAB classification,and accompanied with high white blood cell counts in peripheral blood,high blast counts in bone marrow and low CD34 expression.The older the patients were when diagnosed,the more gene mutations and the higher white blood cell count were detected.More mutations were found in individuals with normal karyotype than that with other karyotypes.It appeared that FLT3-ITD was significantly associated with shorter overall survival (OS) (P =0.004),NPM1 was not significantly associated with OS,but NPM1 +/ITD-patients had the longest OS.Conclusions Our results showed that the mutation types and amounts had particular distribution in MICM subtypes,and were associated with white blood cell counts in peripheral blood,blast counts in bone marrow and prognosis.Especially for patients with normal karyotype,the genetic mutations could be new molecule marker.%目的 探讨急性髓系白血病(AML)患者中C-kit、NPM1、FLT3基因突变的发生率和分布情况,并分析其对预后的影响.方法 应用基因测序方法分别检测656例AML患者C-kit基因8、17号外显子,NPM1基因12号外显子,FLT3基因20(酪氨酸激酶区,TKD)、14、15号外显子(内部串联重复,ITD)基因突变情况,并随访患者的预后.结果 656例AML患者中检出C-kit基因8号外显子突变6例(0.9％),17号外显子突变33例(5.0％),NPM1基因突变169例(25.8％),FLT3-TKD突变46例(7.1％),FLT3-ITD突变178例(27.1％).至少有1个突变的患者341例(50.3％).C-kit的8号外显子检测到6种突变类型；C-kit的17号外显子检测到8种突变类型；NPM1检测到15种突变类型,其中10种类型已有报道(A、B、C、D、Nm、I*、J、J+、S、13),5种类型未见报道；TKD检测到11种突变类型.t(8;21)/M2患者常伴有C-kit的17号外显子突变；inv(16)/M4患者常伴有C-kit的8号外显子突变；M3患者中除FLT3基因突变外未检测到其他突变.NPM1和ITD基因突变多见于正常核型患者,在形态学亚型中多见于M5和M1,阳性病例多伴随高白细胞计数、骨髓原始细胞增多、CD34低表达和CD33高表达.随着发病年龄的增长,突变数量增多,白细胞计数平均值增高,高白细胞计数的患者比例升高.在正常核型的群体中突变阳性的比例较其他群体增高,2种、3种突变的比例增多,差异均有统计学意义(P值均＜0.01).FLT3-ITD突变阳性病例中位生存时间(10.0±1.2)个月,与阴性群体中位生存时间(17.0±2.4)个月相比差异有统计学意义(P =0.004),单独NPM1突变与否对总生存率没有显著影响,但NPM1+/ITD-患者的总生存率最高.结论 C-kit、NPM1、FLT3基因突变类型及数量在MICM分型中都有特殊的分布,并与白细胞计数、骨髓原始细胞数和预后均有相关性.对染色体核型正常的患者,基因突变可作为判断预后新的分子标志.
