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Identifying Secondary Mutations in Chinese Patients with Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs) by Next Generation Sequencing (NGS)

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Pathology & Oncology Research

Abstract

The aim of this study was to characterize secondary kinase mutations in Chinese patients with imatinib-resistant gastrointestinal stromal tumors (GISTs). Mutations in receptor tyrosine kinase (KIT; exons 9, 11, 13, 14, 17, and 18) and platelet-derived growth factor-alpha (PDGFRA; exons 12, 14, and 18) were analyzed by direct sequencing. After imatinib treatment, 425 cancer-related target genes were analyzed by next generation sequencing (NGS) in imatinib-resistant patients. Correlation of sequencing results with clinicopathologic features were analyzed. We identified 320 patients with secondary acquired resistance. We determined that 65.63% (210/320) of resistant patients had secondary KIT mutations in exon 13 (n = 134), exon 14 (n = 10), or exon 17 (n = 66), and 4.38% (14/320) had additional PDGFRA mutations in exon 14 (n = 3) or exon 18 (n = 11). All secondary KIT mutations were missense mutations and were mostly located in kinase domains. Ninety-six imatinib-resistant GIST patients did not have secondary KIT or PDGFRA mutations. Common independent mutation events were found in retinoblastoma protein 1 (RB1) (18/96 cases), SWI/SNF-related matrix associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1) (16/96 cases), and myc-associated factor X (MAX) (10/96 cases). RB1 or SMARCB1 mutations coexisted with activation of other oncogenes in 6 or 15 cases, respectively. Multiple mutations were also seen in cases with MAX mutations. These mutations are frequently associated with clinicopathological factors. Secondary mutations of KIT/PDGFRA were the most important contributors in GISTs developing resistance to imatinib treatment. Additional genetic events including RB1, SMARCB1, and MAX except secondary KIT/PDGFRA mutations are the most common for GISTs to evolve into resistant disease. Clinical assessment of the effect of these mutations may benefit existing risk assessment models and selection of adjuvant therapies in GIST patients.

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Acknowledgements

We thank all patients, physicians, clinical trial nurses, laboratory staff, and technicians for their participation in this study.

Funding

This study was funded by the Natural Science Foundation of the Liaoning province [grant number 20180530045].

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Authors and Affiliations

  1. Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, 110122, People’s Republic of China

    Jiang Du, Rui Wang, Si-Yao Wang, Qiang Han, Hong-Tao Xu, Peng Yang & Yang Liu

  2. Department of Medical Microbiology and Human Parasitology, the College of Basic Medical Sciences of China Medical University, Shenyang, 110122, People’s Republic of China

    Si Wang

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  1. Jiang Du
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  2. Si Wang
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  3. Rui Wang
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  4. Si-Yao Wang
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  5. Qiang Han
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  6. Hong-Tao Xu
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  7. Peng Yang
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  8. Yang Liu
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Contributions

Conceived and designed the experiments: Jiang Du, Yang Liu. Performed the experiments: Si Wang, Rui Wang and Si-Yao Wang. Analyzed the data: Qiang Han, Hong-Tao Xu and Peng Yang. Contributed reagents/materials/ analysis tools: Jiang Du, Hong-Tao Xu, and Yang Liu. Wrote the paper: All authors read and approved the final manuscript.

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Correspondence to Yang Liu.

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The authors declare that they have no competing interests.

Ethics Approval and Informed Consent

This study was approved by the Ethics committee of the First Affiliated Hospital of China Medical University and was performed according to the principles of the Declaration of Helsinki. Written informed consents were obtained from the patients in this study.

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Du, J., Wang, S., Wang, R. et al. Identifying Secondary Mutations in Chinese Patients with Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs) by Next Generation Sequencing (NGS). Pathol. Oncol. Res. 26, 91–100 (2020). https://doi.org/10.1007/s12253-019-00770-6

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