Genomic characterization and outcome evaluation of kinome fusions in lung cancer revealed novel druggable fusions
Abstract Kinase fusions represent an important type of somatic alterations that promote oncogenesis and serve as diagnostic markers in lung cancer. We aimed to identify the landscape of clinically relevant kinase fusions in Chinese lung cancer and to explore rare kinase rearrangements; thus, providi...
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Nature Portfolio
2021
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oai:doaj.org-article:f6cba414f712492aaf01108493a887d12021-12-02T14:58:44ZGenomic characterization and outcome evaluation of kinome fusions in lung cancer revealed novel druggable fusions10.1038/s41698-021-00221-z2397-768Xhttps://doaj.org/article/f6cba414f712492aaf01108493a887d12021-09-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00221-zhttps://doaj.org/toc/2397-768XAbstract Kinase fusions represent an important type of somatic alterations that promote oncogenesis and serve as diagnostic markers in lung cancer. We aimed to identify the landscape of clinically relevant kinase fusions in Chinese lung cancer and to explore rare kinase rearrangements; thus, providing valuable evidence for therapeutic decision making. We performed genomic profiling of 425 cancer-relevant genes from tumor/plasma biopsies from a total of 17,442 Chinese lung cancer patients using next generation sequencing (NGS). Patients’ clinical characteristics and treatment histories were retrospectively studied. A total of 1162 patients (6.66%; 1162/17,442) were identified as having kinase fusions, including 906 adenocarcinomas (ADCs) and 35 squamous cell carcinomas (SCCs). In ADC, 170 unique gene fusion pairs were observed, including rare kinase fusions, SLC12A2-ROS1, NCOA4-RET, and ANK3-RET. As for SCC, 15 unique gene fusions were identified, among which the most frequent were EML4-ALK and FGFR3-TACC3. Analyses of oncogenic mutations revealed a dual role for the gene fusions, CCDC6-RET and FGFR3-TACC3, in driving oncogenesis or serving as acquired resistance mechanisms to kinase inhibitors. In addition, our real-world evidence showed that patients with recurrent kinase fusions with low frequency (two occurrences) could benefit from treatment with kinase inhibitors’ off-label use. Notably, patients with stage IV ADC who had novel RORB-ALK or AFF2-RET fusions, but no other known oncogenic driver mutations, demonstrated favorable clinical outcomes on tyrosine kinase inhibitors. Our data provide a comprehensive overview of the landscape of oncogenic kinase fusions in lung cancer, which assist in recognizing potentially druggable fusions that can be translated into therapeutic applications.Binghao LiHao QuJing ZhangWeibo PanMeng LiuXiaobo YanXin HuangXuexin HeDong LinSisi LiuRuting GuanYong WuQiuxiang OuHua BaoYoubin XuXue WuYang ShaoNong LinNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-9 (2021) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Binghao Li Hao Qu Jing Zhang Weibo Pan Meng Liu Xiaobo Yan Xin Huang Xuexin He Dong Lin Sisi Liu Ruting Guan Yong Wu Qiuxiang Ou Hua Bao Youbin Xu Xue Wu Yang Shao Nong Lin Genomic characterization and outcome evaluation of kinome fusions in lung cancer revealed novel druggable fusions |
| description |
Abstract Kinase fusions represent an important type of somatic alterations that promote oncogenesis and serve as diagnostic markers in lung cancer. We aimed to identify the landscape of clinically relevant kinase fusions in Chinese lung cancer and to explore rare kinase rearrangements; thus, providing valuable evidence for therapeutic decision making. We performed genomic profiling of 425 cancer-relevant genes from tumor/plasma biopsies from a total of 17,442 Chinese lung cancer patients using next generation sequencing (NGS). Patients’ clinical characteristics and treatment histories were retrospectively studied. A total of 1162 patients (6.66%; 1162/17,442) were identified as having kinase fusions, including 906 adenocarcinomas (ADCs) and 35 squamous cell carcinomas (SCCs). In ADC, 170 unique gene fusion pairs were observed, including rare kinase fusions, SLC12A2-ROS1, NCOA4-RET, and ANK3-RET. As for SCC, 15 unique gene fusions were identified, among which the most frequent were EML4-ALK and FGFR3-TACC3. Analyses of oncogenic mutations revealed a dual role for the gene fusions, CCDC6-RET and FGFR3-TACC3, in driving oncogenesis or serving as acquired resistance mechanisms to kinase inhibitors. In addition, our real-world evidence showed that patients with recurrent kinase fusions with low frequency (two occurrences) could benefit from treatment with kinase inhibitors’ off-label use. Notably, patients with stage IV ADC who had novel RORB-ALK or AFF2-RET fusions, but no other known oncogenic driver mutations, demonstrated favorable clinical outcomes on tyrosine kinase inhibitors. Our data provide a comprehensive overview of the landscape of oncogenic kinase fusions in lung cancer, which assist in recognizing potentially druggable fusions that can be translated into therapeutic applications. |
| format |
article |
| author |
Binghao Li Hao Qu Jing Zhang Weibo Pan Meng Liu Xiaobo Yan Xin Huang Xuexin He Dong Lin Sisi Liu Ruting Guan Yong Wu Qiuxiang Ou Hua Bao Youbin Xu Xue Wu Yang Shao Nong Lin |
| author_facet |
Binghao Li Hao Qu Jing Zhang Weibo Pan Meng Liu Xiaobo Yan Xin Huang Xuexin He Dong Lin Sisi Liu Ruting Guan Yong Wu Qiuxiang Ou Hua Bao Youbin Xu Xue Wu Yang Shao Nong Lin |
| author_sort |
Binghao Li |
| title |
Genomic characterization and outcome evaluation of kinome fusions in lung cancer revealed novel druggable fusions |
| title_short |
Genomic characterization and outcome evaluation of kinome fusions in lung cancer revealed novel druggable fusions |
| title_full |
Genomic characterization and outcome evaluation of kinome fusions in lung cancer revealed novel druggable fusions |
| title_fullStr |
Genomic characterization and outcome evaluation of kinome fusions in lung cancer revealed novel druggable fusions |
| title_full_unstemmed |
Genomic characterization and outcome evaluation of kinome fusions in lung cancer revealed novel druggable fusions |
| title_sort |
genomic characterization and outcome evaluation of kinome fusions in lung cancer revealed novel druggable fusions |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/f6cba414f712492aaf01108493a887d1 |
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1718389300180025344 |