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Published on: July 21, 2018
Characterizing kinase intergenic-breakpoint rearrangements in a large-scale lung cancer population and real-world
1Internal Medicine-Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Background:
Kinase gene fusions are strong driver mutations in neoplasia; however, kinase intergenic-breakpoint rearrangements (IGRs) confound the detection of such fusions and of targeted treatments. We aim to provide an overview of kinase IGRs in a large lung cancer cohort and examine real-world survival outcomes of patients with such fusions.
Methods:
Mutational profiles analyzed using targeted next-generation sequencing of 425 cancer-related genes between June 2016 and July 2019 were retrospectively reviewed. Patients' demographic data, clinical characteristics, and survivals were analyzed. RNA sequencing or immunohistochemical assays were carried out to verify chimeric fusion products.
Results:
We identified 3411 patients with kinase fusions from a cohort of 30 450 patients with lung cancer, and 624 kinase IGR events were identified in 538 of the 3411 patients. The most frequently identified kinase genes included anaplastic lymphoma kinase (ALK), RET proto-oncogene (RET), ROS proto-oncogene 1 (ROS1), Erb-B2 receptor tyrosine kinase 2/3 (ERBB2/3), and epidermal growth factor receptor (EGFR). Our data showed that most (67%) kinase IGRs occurred on the same chromosome and kinase domains remained intact at the 3'-end. Approximately 3% (19/624) of the kinase IGRs had one genomic breakpoint located in gene promoter regions, including nine fusion events involving ALK, RET, ROS1, EGFR, ERBB2, or fibroblast growth factor receptor 3 (FGFR3). Among the 538 patients with kinase IGRs, 167 (31%) lacked oncogenic driver mutations, among which 28 received targeted therapies in real-world practice. Notably, three ALK IGR patients who harbored no canonical oncogenic aberrations were confirmed with an EML4-ALK chimeric fusion product by RNA sequencing and/or ALK immunohistochemical assays. One patient demonstrated a favorable clinical outcome after 14 months on crizotinib. An additional two patients who had ROS1 IGRs demonstrated a clinical benefit after 13 and 19 months on crizotinib, respectively.
Conclusion:
A large real-world lung cancer cohort with kinase IGRs was comprehensively analyzed for their molecular characteristics. The data indicated the potential oncogenic function of kinase IGRs and their outcomes following the administration of targeted therapies.
Insights
Kinase intergenic-breakpoint rearrangements (IGRs) in lung cancer can be oncogenic drivers. Some patients with kinase IGRs lacking other drivers benefited from targeted therapies like crizotinib.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Kinase gene fusions are key drivers in cancer.
- Kinase intergenic-breakpoint rearrangements (IGRs) complicate the identification of fusions and targeted treatments.
- Understanding kinase IGRs in lung cancer is crucial for effective therapy.
Purpose of the Study:
- To analyze kinase IGRs in a large lung cancer cohort.
- To investigate real-world survival outcomes for patients with kinase IGRs.
- To assess the impact of targeted therapies on patients with kinase IGRs.
Main Methods:
- Retrospective analysis of mutational profiles from targeted next-generation sequencing (425 genes) in 30,450 lung cancer patients.
- Identification and characterization of kinase IGRs.
- RNA sequencing and immunohistochemical assays for fusion product verification.
- Analysis of demographic, clinical, and survival data.
Main Results:
- 624 kinase IGR events were found in 538 of 3411 patients with kinase fusions.
- Anaplastic Lymphoma Kinase (ALK), RET, ROS1, ERBB2/3, and EGFR were frequently involved.
- Approximately 3% of IGRs involved gene promoter regions, with nine fusion events identified.
- 167 patients (31%) with IGRs lacked other driver mutations; 28 received targeted therapy.
- Three ALK IGR patients with no canonical drivers showed EML4-ALK fusion and responded to crizotinib; two ROS1 IGR patients also benefited.
Conclusions:
- Kinase IGRs represent a significant molecular event in lung cancer.
- These rearrangements may possess oncogenic function.
- Targeted therapies can be effective in a subset of patients with kinase IGRs, even in the absence of canonical drivers.
