Abstract 2211: The landscape and implications of kinase-intergenic fusions in a large real-world lung cancer cohort
Authors: Ma Yutong , Ou Qiuxiang , Wu Xue , Shao Yang 
Published: July 2021

Abstract
Background: Kinase gene fusions are strong driver mutations in neoplasia and have provided fundamental insights into the disease mechanisms that are involved in tumorigenesis. Into the era of next generation sequencing (NGS), numerous studies have described fusion events with breakpoints occurring at two intragenic positions that result in in-frame gene-gene fusions, but fusions that occur with intergenic regions are not uncommon. The clinical significance of such fusions needs to be carefully examined.
Methods: We retrospectively reviewed the mutation profiles of over 30 000 lung cancer patients whose tissue and/or plasma samples underwent targeted NGS from June 2016 to July 2019. Clinical data of patients who had kinase-intergenic fusions were retrieved for analysis. RNA sequencing and immunohistochemical (IHC) assays were performed to verify chimeric fusion products on the transcriptional or protein level.
Results: A total of 624 kinase-intergenic fusion events were identified in 538 unique lung cancer patients. Approximately 75% (404/538) of the entire cohort were non-small cell lung cancer (NSCLC), and 93% (375/404) of NSCLC were adenocarcinoma. The most frequently identified kinase genes included ALK, RET, ROS1, ERBB2/3, EGFR, FGFR1/2/3, and NTRK1/2/3. Our data showed that most (67%) kinase-intergenic gene rearrangements occurred on the same chromosome and kinase domains remained intact at 3' end. About 3% (19/624) of the kinase-intergenic fusions had one genomic breakpoint located in promoter regions, including 9 events involving ALK, RET, ROS1, EGFR, ERBB2, and FGFR3, which were fused to different gene promoters that may result in changes in kinase gene transcription. Importantly, 371 patients (69%) had concurrent oncogenic driver mutations or intragenic fusions, but the remaining 167 patients (31%) had kinase-intergenic fusions detected solely without other known oncogenic aberrations. Noteworthy, three patients who had ALK-intergenic fusions, but no other known oncogenic aberrations, were confirmed of EML4-ALK chimeric fusion product by RNA sequencing and/or ALK IHC results. Among them, one patient achieved a durable response of 14-month on crizotinib. An additional two patients who had ROS1 intergenic fusions demonstrated clinical benefit of 11 and 19 months from crizotinib, respectively, but the underlying functional fusion products remained to be further determined.
Conclusion: This study investigated the role of kinase-intergenic fusions on a large-scale lung cancer population and revealed the potential oncogenic function of kinase-intergenic fusions. Our data also suggested that in addition to DNA sequencing, additional validation testing using RNA and/or protein assay should be performed in intergenic-breakpoint fusion cases to guide optimal treatment.
Citation Format: Yutong Ma, Qiuxiang Ou, Xue Wu, Yang Shao. The landscape and implications of kinase-intergenic fusions in a large real-world lung cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2211.