Objective: To investigate the spectrum of gene mutations in adult patients with B-acute lymphoblastic leukemia (B-ALL), and to analyze the influences of different gene mutations on prognosis. Methods: DNA samples from 113 adult B-ALL patients who administered from June 2009 to September 2015 were collected. Target-specific next generation sequencing (NGS) approach was used to analyze the mutations of 112 genes (focused on the specific mutational hotspots) and all putative mutations were compared against multiple databases to calculate the frequency spectrum. The impact of gene mutation on the patients' overall survival (OS) and recurrence free survival (RFS) was analyzed by the putative mutations through Kaplan-Meier, and Cox regression methods. Results: Of the 113 patients, 103 (92.0%) harbored at least one mutation and 29 (25.6%) harbored more than 3 genes mutation. The five most frequently mutated genes in B-ALL are SF1, FAT1, MPL, PTPN11 and NRAS. Gene mutations are different between Ph+ B-ALL and Ph- B-ALL patients. Ph- B-ALL patients with JAK-STAT signal pathway related gene mutation, such as JAK1/JAK2 mutation showed a poor prognosis compared to the patients without mutation (OS: P=0.011, 0.001; RFS: P=0.014,<0.001). Patients with PTPN11 mutation showed better survival than those without mutation, but the difference was not statistically significant (P value > 0.05). Besides, in Ph+ B-ALL patients whose epigenetic modifications related signaling pathway genes were affected, they had a worse prognosis (OS: P=0.038; RFS: P=0.047). Conclusion: Gene mutations are common in adult ALL patients, a variety of signaling pathways are involved. The frequency and spectrum are varied in different types of B-ALL. JAK family gene mutation usually indicates poor prognosis. The co-occurrence of somatic mutations in adult B-ALL patients indicate the genetic complex and instability of adult B-ALL patients.
目的： 探讨成人急性B淋巴细胞白血病（B-ALL）患者的基因突变谱，并分析其对患者预后的影响。 方法： 收集113例2009年6月至2015年9月收治的成人B-ALL患者DNA标本，采用靶向特异的二代测序技术，针对血液恶性疾病相关的112种基因进行突变分析，通过多个数据库筛选出可能致病的基因突变，描述其发生频谱，并通过Kaplan-Meier、Cox回归模型分析突变基因对患者总生存（OS）和无复发生存（RFS）的影响。 结果： 113例患者中103例（92.0%）发生至少一种基因突变，29例（25.6%）患者发生≥3种基因突变。所有患者中突变率较高的基因有SF1、FAT1、MPL、PTPN11、NRAS等，Ph阳性B-ALL和Ph阴性B-ALL患者中基因突变特点不尽一致。进一步分析基因突变对患者预后的影响，发现在Ph阴性B-ALL中伴JAK-STAT信号通路相关基因突变的患者（如JAK1、JAK2突变）较该信号通路未受影响的患者预后差（OS：P值分别为0.011和0.001；RFS：P值分别为0.014和<0.001），而伴PTPN11突变的B-ALL患者较不伴PTPN11突变的患者有较好的OS及RFS，但差异无统计学意义（P值均>0.05）；在Ph阳性B-ALL患者中，表观遗传学修饰相关的信号通路异常的患者预后较差（OS：P=0.038；RFS：P=0.047）。 结论： 基因突变在成人B-ALL中存在普遍性，发生频谱因亚型而异，涉及多种信号通路，JAK家族相关基因突变常提示患者预后较差，突变基因之间的共存现象也预示着成人B-ALL患者的遗传复杂性和不稳定性。.
Keywords: DNA mutational analysis; Leukemia, B-cell; Prognosis; Target-specific next-generation sequencing.