Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib
Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib
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DOI：
10.1002/ijc.32502
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发表时间：
2020-01-01
影响因子：
6.4
通讯作者：
Bodor, Csaba
中科院分区：
文献类型：
--
作者：
Gango, Ambrus;Alpar, Donat;Bodor, Csaba
布鲁顿氏酪氨酸激酶 (BTK) 抑制剂依鲁替尼在难治性/复发性疾病或 TP53 缺陷的慢性淋巴细胞白血病 (CLL) 患者中诱导持久反应，其中 BTK 和磷脂酶 C γ 2 (PLCG2) 突变代表了依鲁替尼继发性耐药的主要机制。为了了解与依鲁替尼治疗相关的基因组变化情况和亚克隆结构的动态，对 20 名患者的连续样本（在单药依鲁替尼治疗之前和期间收集）进行了 30 个反复突变基因的超深度下一代测序分析。 SF3B1、MGA 和 BIRC3 基因的突变在依鲁替尼治疗期间富集，而 BTK、PLCG2、RIPK1、NFKBIE 和 XPO1 基因的畸变仅在治疗后样本中检测到。除了典型突变外，还发现了四种新的 BTK 突变和三种先前未报告的 PLCG2 变体。使用数字液滴 PCR 在 5 名患者中回溯了 BTK 和 PLCG2 突变，并且在临床复发前平均 10.5 个月可检测到。中位随访时间为 36.5 个月，7/9 携带 BTK 突变的患者根据临床和/或实验室特征显示疾病进展。总之，在接受依鲁替尼治疗的个体患者中，亚克隆异质性、动态克隆选择和各种克隆变异模式与新的耐药相关 BTK 突变相关。
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is inducing durable responses in chronic lymphocytic leukemia (CLL) patients with refractory/relapsed disease or with TP53 defect, with BTK and phospholipase C gamma 2 (PLCG2) mutations representing the predominant mechanisms conferring secondary ibrutinib resistance. To understand the landscape of genomic changes and the dynamics of subclonal architecture associated with ibrutinib treatment, an ultra-deep next-generation sequencing analysis of 30 recurrently mutated genes was performed on sequential samples of 20 patients, collected before and during single-agent ibrutinib treatment. Mutations in the SF3B1, MGAand BIRC3 genes were enriched during ibrutinib treatment, while aberrations in the BTK, PLCG2, RIPK1, NFKBIE and XPO1 genes were exclusively detected in posttreatment samples. Besides the canonical mutations, four novel BTK mutations and three previously unreported PLCG2 variants were identified. BTK and PLCG2 mutations were backtracked in five patients using digital droplet PCR and were detectable on average 10.5 months before clinical relapse. With a median follow-up time of 36.5 months, 7/9 patients harboring BTK mutations showed disease progression based on clinical and/or laboratory features. In conclusion, subclonal heterogeneity, dynamic clonal selection and various patterns of clonal variegation were identified with novel resistance-associated BTK mutations in individual patients treated with ibrutinib.