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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Integrative Genomic Analysis Reveals Cancer-Associated Gene Mutations in Chronic Myeloid Leukemia Patients with
1Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, People's Republic of China.
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.
Insights
Genetic mutations beyond ABL1 kinase domain (KD) are common in chronic myeloid leukemia (CML) patients with tyrosine kinase inhibitor (TKI) resistance or intolerance. Next-generation sequencing (NGS) aids in identifying these mutations for better risk stratification.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) is often linked to ABL1 kinase domain (KD) mutations.
- However, genetic alterations beyond ABL1 KD mutations may also drive CML progression and treatment failure.
Purpose of the Study:
- To investigate the spectrum of genetic mutations in CML patients experiencing TKI resistance or intolerance.
- To identify novel genetic markers associated with TKI resistance, intolerance, and patient prognosis.
Main Methods:
- Targeted-capture sequencing of 127 cancer-related genes was performed on 63 CML patients.
- The patient cohort included 42 individuals with TKI resistance and 21 with TKI intolerance.
- Next-generation sequencing (NGS) was employed for comprehensive genetic analysis.
Main Results:
- 66 mutations were identified in 96.8% of patients, frequently in KTM2C, ABL1, FAT1, and ASXL1 genes.
- Mutations in CUX1, KIT, and GATA2 were associated with TKI intolerance, with CUX1 and GATA2 being transcription factors.
- ASXL1 mutations were more prevalent in patients with ABL1 KD mutations (38.1% vs 15.21%, P=0.041).
- TET2 mutations correlated with shorter progression-free survival (P=0.026).
Conclusions:
- CUX1, KIT, and GATA2 mutations may contribute significantly to TKI intolerance in CML.
- ASXL1 and TET2 mutations are potential indicators of poor prognosis in CML patients.
- NGS-based genetic profiling enhances clinical risk stratification for CML patients undergoing TKI therapy.
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