25P Identification of novel kinase-activating fusions in non-small cell lung carcinomas (NSCLCs)

Abstract

Gene fusions involving protein kinases are druggable targets characteristic for a subset of NSCLCs. NGS analysis for 650 kinase genes was performed for 38 RNA lung adenocarcinomas obtained from young-onset patients (age range: 33-50 years; median age: 44 years; 22 males and 16 females). All these tumors were negative for activating events involving EGFR, ALK, ROS1, RET, MET, NTRK1/2/3, BRAF, HER2 and KRAS genes. Kinome RNAseq revealed 67 chimeric transcripts in 38 NSLC cases. Five of these chimeras were recurrent, being a result of large intrachromosomal rearrangements and observed in 2-19 tumors each; however, none of these translocations predicted for a protein product. The majority of aberrations were frameshift mutations. 18 fusion variants were in-frame, but only four rearrangements preserved the entire kinase domain within a chimeric transcript: BCR-PKHD1 t(22;6)(q11.23;p12.3), CLTC-RPS6KB1 17q23.1del0.2Mb, CDC42BPG-ATG2A 11q13.1del0.05Mb and MAPRE1-DGKB t(20;7)(q11.21;p21.2). By the time of the abstract submission, BCR-PKHD1 and recently reported CLIP1-LTK [Izumi et al., 2021, PMID 34819663] gene fusions were analyzed in 2754 NSCLCs, which were negative for all known actionable mutations, however no new instances of these translocations have been observed. This study has not replicated the data on the frequent involvement of CLIP1-LTK fusions in NSCLCs, however identified a number of other kinase gene fusions deserving further investigation.