TP53和JAK2基因的突变是B细胞前体急性淋巴细胞白血病中独立的预后生物标志物。
Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia.
作者信息
Forero-Castro Maribel, Robledo Cristina, Benito Rocío, Bodega-Mayor Irene, Rapado Inmaculada, Hernández-Sánchez María, Abáigar María, Maria Hernández-Sánchez Jesús, Quijada-Álamo Miguel, María Sánchez-Pina José, Sala-Valdés Mónica, Araujo-Silva Fernanda, Kohlmann Alexander, Luis Fuster José, Arefi Maryam, de Las Heras Natalia, Riesco Susana, Rodríguez Juan N, Hermosín Lourdes, Ribera Jordi, Camos Guijosa Mireia, Ramírez Manuel, de Heredia Rubio Cristina Díaz, Barragán Eva, Martínez Joaquín, Ribera José M, Fernández-Ruiz Elena, Hernández-Rivas Jesús-María
机构信息
IBSAL, IBMCC, University of Salamanca, CSIC, Cancer Research Center, Campus Miguel de Unamuno, Salamanca 37007, Spain.
School of Biological Sciences (GICBUPTC research group), Universidad Pedagógica y Tecnológica de Colombia (UPTC), Avenida Central del Norte 39-115, Tunja 150003, Colombia.
出版信息
Br J Cancer. 2017 Jul 11;117(2):256-265. doi: 10.1038/bjc.2017.152. Epub 2017 May 30.
BACKGROUND
In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols.
METHODS
Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR).
RESULTS
A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P=0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 (P=0.047) or BCR-ABL1 fusions (P<0.0001). In children, TP53mut was associated with lower OS (5-year OS: 50% vs 86%, P=0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P=0.009) and higher RR (5-year RR: 33.3% vs 18.6% P=0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P=0.04). In adults, TP53mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P=0.019) and a higher RR (5-year RR: 100% vs 61.4%, P=0.029), whereas JAK2mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P=0.035) and a higher RR (5-year RR: 100% vs 60.4%, P=0.002). TP53mut was an independent risk factor for shorter OS (HR=2.3; P=0.035) and, together with JAK2mut, also were independent markers of poor prognosis for RR (TP53mut: HR=5.9; P=0.027 and JAK2mut: HR=5.6; P=0.036).
CONCLUSIONS
TP53mut and JAK2mut are potential biomarkers associated with poor prognosis in B-ALL patients.
背景
在B细胞前体急性淋巴细胞白血病（B-ALL）中，识别与预后不良相关的其他基因改变仍然很重要。我们确定了采用西班牙PETHEMA和SEHOP方案治疗的儿童和成人B-ALL病例中体细胞突变的频率及其预后影响。
方法
通过下一代深度测序确定了340例B-ALL患者（211例儿童和129例成人）中TP53、JAK2、PAX5、LEF1、CRLF2和IL7R基因热点区域的突变状态。评估了突变状态与诊断时的临床病理特征、治疗结果和生存之间的关联。进行单因素和多因素生存分析以确定与总生存期（OS）、无事件生存期（EFS）和复发率（RR）相关的独立预后因素。
结果
确定突变率为12.4%。成人的突变频率更高（20.2%对7.6%，P=0.001）。TP53是最常发生突变的基因（4.1%），其次是JAK2（3.8%）、CRLF2（2.9%）、PAX5（2.4%）、LEF1（0.6%）和IL7R（0.3%）。所有突变均在无ETV6-RUNX1（P=0.047）或BCR-ABL1融合（P<0.0001）的B-ALL中观察到。在儿童中，TP53突变与较低的OS（5年OS：50%对86%，P=0.002）和EFS率（5年EFS：50%对78.3%，P=0.009）以及较高的RR（5年RR：33.3%对18.6%，P=0.037）相关，并且与较高的RR独立相关（风险比（HR）=4.5；P=0.04）。在成人中，TP53突变与较低的OS（5年OS：0%对43.3%，P=0.019）和较高的RR（5年RR：100%对61.4%，P=0.029）相关，而JAK2突变与较低的EFS（5年EFS：0%对30.6%，P=0.035）和较高的RR（5年RR：100%对60.4%，P=0.002）相关。TP53突变是OS缩短的独立危险因素（HR=2.3；P=0.035），并且与JAK2突变一起，也是RR预后不良的独立标志物（TP53突变：HR=5.9；P=0.027和JAK2突变：HR=5.6；P=0.036）。
结论
TP53突变和JAK2突变是与B-ALL患者预后不良相关的潜在生物标志物。
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