Mutations and Deletions of the TP53 Gene Predict Nonresponse to Treatment and Poor Outcome in First Relapse of Childhood Acute Lymphoblastic Leukemia
Mutations and Deletions of the TP53 Gene Predict Nonresponse to Treatment and Poor Outcome in First Relapse of Childhood Acute Lymphoblastic Leukemia
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DOI：
10.1200/jco.2011.34.8144
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发表时间：
2011-08-10
影响因子：
45.3
通讯作者：
Kirschner-Schwabe, Renate
中科院分区：
文献类型：
--
作者：
Hof, Jana;Krentz, Stefanie;Kirschner-Schwabe, Renate
目的在儿童复发性急性淋巴细胞白血病（ALL）的临床治疗中，耐药仍然是一个主要的挑战。TP 53基因的改变通常与化疗耐药有关，但由于小规模研究，其在复发性儿童ALL中的意义仍存在争议。我们系统地研究了2002年德国急性淋巴细胞白血病复发柏林-法兰克福-明斯特265例首次复发患者（ALL-REZ BFM 2002）的试验，通过使用直接测序和多重连接依赖探针扩增来检测TP 53基因的序列和拷贝数的改变。（27/218）的B细胞前体ALL患者和6.4%（3/47）的T细胞ALL患者复发。在23个匹配的样本中回溯到初始ALL，发现所有TP 53改变中的54%在复发时获得。在前体B细胞ALL中，TP 53改变与化疗无反应（P <0.001）、无事件生存率（P <0.001）和总生存率（P = 0.002）相关。TP 53改变也对中危（S2）和高危（S3/S4）复发患者的生存率有显著影响（分别为P = 0.007和P = 0.019）。TP 53改变的预后意义在多变量分析中得到证实。除了他们的临床影响，TP 53的改变与较高比例的白血病细胞在S/G（2）-M期的细胞周期在复发diagnosis. Conclusionalrations的TP 53基因是特别重要的复发阶段的儿童ALL，在他们独立预测高风险的治疗失败的显着数量的患者。因此，它们将有助于未来对ALL复发儿童的风险评估。
PurposeIn the clinical management of children with relapsed acute lymphoblastic leukemia (ALL), treatment resistance remains a major challenge. Alterations of the TP53 gene are frequently associated with resistance to chemotherapy, but their significance in relapsed childhood ALL has remained controversial because of small studies.Patients and MethodsTherefore, we systematically studied 265 first-relapse patients enrolled in the German Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Munster 2002 (ALL-REZ BFM 2002) trial for sequence and copy number alterations of the TP53 gene by using direct sequencing and multiplex ligation-dependent probe amplification.ResultsWe observed copy number and sequence alterations of TP53 in 12.4% (27 of 218) of patients with B-cell precursor ALL and 6.4% (three of 47) of patients with T-cell ALL relapse. Backtracking to initial ALL in 23 matched samples revealed that 54% of all TP53 alterations were gained at relapse. Within B-cell precursor ALL, TP53 alterations were consistently associated with nonresponse to chemotherapy (P < .001) and poor event-free survival (P < .001) and overall survival rates (P = .002). TP53 alterations also had a significant impact on survival within intermediate-risk (S2) and high-risk (S3/S4) relapse patients (P = .007 and P = .019, respectively). This prognostic significance of TP53 alterations was confirmed in multivariate analysis. Besides their clinical impact, TP53 alterations were associated with a higher fraction of leukemic cells in S/G(2)-M phase of the cell cycle at relapse diagnosis.ConclusionAlterations of the TP53 gene are of particular importance in the relapse stage of childhood ALL, in which they independently predict high risk of treatment failure in a significant number of patients. Therefore, they will aid in future risk assessment of children with ALL relapse.