Integrative Genomic Analysis Reveals Cancer-Associated Gene Mutations in Chronic Myeloid Leukemia Patients with Resistance or Intolerance to Tyrosine Kinase Inhibitor
Integrative Genomic Analysis Reveals Cancer-Associated Gene Mutations in Chronic Myeloid Leukemia Patients with Resistance or Intolerance to Tyrosine Kinase Inhibitor
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综合基因组分析揭示对酪氨酸激酶抑制剂耐药或不耐受的慢性粒细胞白血病患者中的癌症相关基因突变
DOI：
10.2147/ott.s257661
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Liu, Xiaoli
中科院分区：
文献类型：
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作者：
Wu, Waner;Xu, Na;Liu, Xiaoli
虽然ABL1激酶结构域（KD）突变的获得已被确定为酪氨酸激酶抑制剂（TKI）耐药背后的共同机制，但最近的遗传学研究表明，TKI耐药或不耐受患者经常伴有一种或多种与髓系恶性肿瘤相关的遗传改变。这表明ABL1 KD突变以外的其他突变可能有助于疾病进展。方法采用新一代测序技术（NGS）对63例CML患者的127个已知和推测的癌症相关基因进行靶向捕获测序，其中42例TKI耐药患者和21例TKI不耐受患者。结果两组间突变数差异无统计学意义。这可以部分解释为并非所有患者在早期都达到预期的主要分子缓解。总体而言，在96.8%的患者中鉴定出66个突变，最常见的是KTM2C（31.82%）、ABL1（31.82%）、FAT1（25.76%）和ASXL1（22.73%）基因。CUX1， KIT和GATA2与TKI不耐受相关，其中两个（CUX1, GATA2）是在82.61%的TKI不耐受患者中发现突变的转录因子。ASXL1突变在ABL1 KD突变患者中更为常见（38.1% vs 15.21%， P=0.041）。虽然突变数量较少，但突变基因间的两两互作表明ABL1 KD突变与SH2B3突变同时发生（P<0.05）。在Kaplan-Meier分析中，只有TET2突变与较短的无进展生存期相关（P=0.026）。结论CUX1、KIT和GATA2基因可能在TKI不耐受中起重要作用。ASXL1和TET2突变可能与患者预后不良有关。NGS有助于改善临床风险分层，使TKI治疗时代的TKI耐药或不耐受患者得以识别。
Introduction While the acquisition of mutations in the ABL1 kinase domain (KD) has been identified as a common mechanism behind tyrosine kinase inhibitor (TKI) resistance, recent genetic studies have revealed that patients with TKI resistance or intolerance frequently harbor one or more genetic alterations implicated in myeloid malignancies. This suggests that additional mutations other than ABL1 KD mutations might contribute to disease progression. Methods We performed targeted-capture sequencing of 127 known and putative cancer-related genes of 63 patients with CML using next-generation sequencing (NGS), including 42 patients with TKI resistance and 21 with TKI intolerance. Results The differences in the number of mutations between groups had no statistical significance. This could be explained in part by not all of the patients having achieved major molecular remission in the early period as expected. Overall, 66 mutations were identified in 96.8% of the patients, most frequently in the KTM2C (31.82%), ABL1 (31.82%), FAT1 (25.76%), and ASXL1 (22.73%) genes. CUX1, KIT, and GATA2 were associated with TKI intolerance, and two of them (CUX1, GATA2) are transcription factors in which mutations were identified in 82.61% of patients with TKI intolerance. ASXL1 mutations were found more frequently in patients with ABL1 KD mutations (38.1% vs 15.21%, P=0.041). Although the number of mutations was low, pairwise interaction between mutated genes showed that ABL1 KD mutations cooccurred with SH2B3 mutations (P<0.05). In Kaplan–Meier analyses, only TET2 mutations were associated with shorter progression-free survival (P=0.026). Conclusion Our data suggested that the CUX1, KIT, and GATA2 genes may play important roles in TKI intolerance. ASXL1 and TET2 mutations may be associated with poor patient prognosis. NGS helps improving the clinical risk stratification, which enables the identification of patients with TKI resistance or intolerance in the era of TKI therapy.