Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia
Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia
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治疗诱导的突变驱动复发性急性淋巴细胞白血病的基因组景观
DOI：
10.1182/blood.2019002220
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发表时间：
2020-01-02
期刊：
影响因子：
20.3
通讯作者：
Zhang, Jinghui
中科院分区：
文献类型：
--
作者：
Li, Benshang;Brady, Samuel W.;Zhang, Jinghui
为了研究急性淋巴细胞白血病（ALL）复发的机制，我们对16例患者的103个诊断-复发-生殖系三联体进行了全基因组测序，并对208个系列样本进行了超深度测序。复发特异性体细胞改变富集在参与药物反应的12个基因（NR 3C 1、NR 3C 2、TP 53、NT 5C 2、FPGS、CREBBP、MSH 2、MSH 6、PMS 2、WHSC 1、PRPS 1和PRPS 2）中。在极早期复发（36个月）组中，其患病率为17%。在6例复发病例中观察到多个亚克隆在同一耐药基因中携带突变的趋同进化，并在1例病例中通过单细胞测序证实。数学建模和突变特征分析表明，早期复发抗性的获得通常是一个2步过程，其中持续性克隆在初始治疗中存活，随后在治疗期间获得真正的抗性突变。相反，极早期复发来自预先存在的耐药克隆。在早期和晚期复发中发现了两种新的复发特异性突变特征，其中一种是由基于体外药物暴露实验的巯基嘌呤治疗引起的，但在2540个泛癌症诊断样本和129个非ALL复发中不存在。在27%的复发性ALL中检测到了新的特征，并导致了NT 5C 2、PRPS 1、NR 3C 1和TP 53中46%的获得性耐药突变。这些结果表明，化疗诱导的耐药突变促进了儿童ALL复发的一个子集。
To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.