Feng J, Gong X Y, Jia Y J, Liu K Q, Li Y, Dong X B, Fang Q Y, Ru K, Li Q H, Wang H J, Zhao X L, Jia Y N, Song Y, Tian Z, Wang M, Tang K J, Wang J X, Mi Y C
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
Zhonghua Xue Ye Xue Za Zhi. 2018 Feb 14;39(2):98-104. doi: 10.3760/cma.j.issn.0253-2727.2018.02.004.
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. 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. 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: =0.011, 0.001; RFS: =0.014,<0.001). Patients with PTPN11 mutation showed better survival than those without mutation, but the difference was not statistically significant ( value > 0.05). Besides, in Ph B-ALL patients whose epigenetic modifications related signaling pathway genes were affected, they had a worse prognosis (OS: =0.038; RFS: =0.047). 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.
旨在研究成人B淋巴细胞白血病（B-ALL）患者的基因突变谱，并分析不同基因突变对预后的影响。收集了2009年6月至2015年9月收治的113例成人B-ALL患者的DNA样本。采用靶向特异性二代测序（NGS）方法分析112个基因的突变情况（聚焦于特定突变热点），并将所有推定突变与多个数据库进行比对以计算频率谱。通过Kaplan-Meier法和Cox回归方法，分析推定突变对患者总生存期（OS）和无复发生存期（RFS）的影响。113例患者中，103例（92.0%）至少存在一种突变，29例（25.6%）存在3种以上基因突变。B-ALL中最常发生突变的5个基因是SF1、FAT1、MPL、PTPN11和NRAS。Ph+B-ALL和Ph-B-ALL患者的基因突变情况不同。与未发生突变的患者相比，发生JAK-STAT信号通路相关基因突变（如JAK1/JAK2突变）的Ph+B-ALL患者预后较差（OS：P=0.011，P<0.001；RFS：P=0.014，P<0.001）。发生PTPN11突变的患者生存率高于未发生突变的患者，但差异无统计学意义（P值>0.05）。此外，在表观遗传修饰相关信号通路基因受影响的Ph+B-ALL患者中，其预后较差（OS：P=0.038；RFS：P=0.047）。基因突变在成人ALL患者中很常见，涉及多种信号通路。不同类型的B-ALL中，基因突变的频率和谱各不相同。JAK家族基因突变通常提示预后不良。成人B-ALL患者体细胞突变的共现表明成人B-ALL患者的基因复杂性和不稳定性。
