Genomic characterization and outcome evaluation of kinome fusions in a large non-small cell lung cancer population.

Abstract

9620 Background: Lung cancer is the leading cause of cancer death worldwide. Kinase fusion represents an important type of somatic alterations which promote oncogenesis and serve as a diagnostic marker in lung cancer. This study aims to identify the landscape of kinase fusions in lung cancer and expand our understanding of druggable fusions, together providing valuable information for therapeutics decision making. Methods: We performed genomic profiling of tumor/plasma biopsies of a total of 18,839 Chinese lung cancer patients using next generation sequencing (NGS) by targeting 425 cancer-relevant genes. Patients’ clinical characteristics and treatment history were retrospectively studied. Results: A total of 1,048 patients (5.56%, 1,048/18,839) were identified with kinase fusions, including 815 adenocarcinomas (ADCs) and 34 squamous cell carcinomas (SCCs). Briefly, a total of 198 unique gene fusion events have been observed, including 37 recurrent fusions and 114 novel fusions which have previously not been documented. ADC patients with kinase fusions were relatively younger than SCC patients (median: 53 vs 61 years old, p< 0.01). The most frequently observed fusion was EML4-ALK for both ADCs (50.0%) and SCCs (32.4%), followed by FGFR3-TACC3 (29.4%) in SCCs and KIF5B-RET (11.8%), CD74-ROS1 (9.2%), CCDC6-RET (3.9%) and SLC34A2-ROS1 (2.3%) in ADCs, retrospectively. A total of 14 recurrent fusions including FN1-ALK, MEMO1-ALK, CUX1-ALK, KIF13A-RET and PHF20-NTRK1 were also identified at low frequencies. Of note, EML4- or STRN- ALK fusion events mainly rearranged in the intron 19 of ALK, but the breakpoints of VCL-ALK were mostly located upstream of ALK exon 18. Meanwhile, CD74-, SLC34A2- and TPM3- ROS1 rearrangement mainly occurred in the ROS1 introns 31, 33 and 34. In addition, among patients with novel fusions, RORB- ALK and AFF2-RET may potentially function as oncogenic drivers in lung cancer and have demonstrated clinical benefit from crizotinib treatment. Conclusions: Our data have depicted a comprehensive overview of the landscape of kinase fusions in lung cancer, which helps recognize potentially druggable fusions and translate into therapeutic applications.