Integrative Genomic Analysis Reveals Cancer-Associated Gene Mutations in Chronic Myeloid Leukemia Patients with Resistance or Intolerance to Tyrosine Kinase Inhibitor

Waner Wu; Na Xu; Xuan Zhou; Liang Liu; Yaxian Tan; Jie Luo; Jixian Huang; Jiayue Qin; Juan Wang; Zhimin Li; Changxin Yin; Lingling Zhou; Xiaoli Liu

doi:10.2147/OTT.S257661

Integrative Genomic Analysis Reveals Cancer-Associated Gene Mutations in Chronic Myeloid Leukemia Patients with Resistance or Intolerance to Tyrosine Kinase Inhibitor

Onco Targets Ther. 2020 Aug 25:13:8581-8591. doi: 10.2147/OTT.S257661. eCollection 2020.

Authors

Waner Wu^#¹, Na Xu^#¹, Xuan Zhou¹, Liang Liu¹, Yaxian Tan¹, Jie Luo¹, Jixian Huang², Jiayue Qin³, Juan Wang³, Zhimin Li³, Changxin Yin¹, Lingling Zhou¹, Xiaoli Liu¹

Affiliations

¹ Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, People's Republic of China.
² Department of Hematology, Yuebei People's Hospital, Shantou University, Shaoguan 512025, Guangdong, People's Republic of China.
³ Yiwu Cancer Research Center, Fudan University Shanghai Cancer Center, Yiwu, Zhejiang 322000, People's Republic of China.

^# Contributed equally.

Abstract

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.

Keywords: chronic myeloid leukemia; intolerance; mutations; resistance; tyrosine kinase inhibitor.

Grants and funding

This study was supported by the National Natural Science Foundation of China [No. 81700104]; Science Foundation of Nan fang Hospital [2016A002]; the National Natural Science Foundation of Guangdong Province, China [2017A030313506]; the Science and Technology Foundation of Guangzhou, China [201904010488]; the National Natural Science Foundation of China [No. 81700162]; the National Natural Science Foundation of Guangdong Province, China [2017A020215047]; the Medical Scientific Research Foundation of Guangdong Province, China [No. 2017cx/008].