Frequency and functional characterization of fusion genes in squamous cell carcinoma of the lung

•Targeted NGS analysis of 1608 LUSC cases revealed that 3 % have gene fusions.•EGFR-VSTM2A fusions appear simultaneously with amplifications of EGFR.•LUSC patients show chromosomally unstable genomes.•Biological relevance of fusions in LUSC patients must be investigated in each case. In contrast to lung adenocarcinoma (LUAD), targetable genetic alterations are less frequently detected in squamous cell carcinoma of the lung (LUSC). Over the last years, gene fusions have become promising targets in many solid cancers. Here, we analysed a cohort of LUSC, identified recurrent fusion genes and functionally characterised these tumour genomes. A subset of 1608 squamous cell carcinomas of the lung was analysed by means of the FusionPlex® Lung Panel to identify potentially targetable gene fusions using targeted next-generation sequencing. Cases harbouring recurrent gene fusions were further analysed using FISH, Cytoscan HD arrays and cell culture experiments. We found both, known and novel gene fusions in about 3 % of the cases. Known fusions occurring in lung cancer included ALK::EML4, EGFRvIII, EZR::ROS1 and FGFR3::TACC. We further identified recurrent gene fusions of currently unknown biological function, involving EGFR::VSTM2A and NSD3::FGFR1 and showed that the occurrence of the EGFR::VSTM2A fusion is accompanied by high-level amplification of EGFR. Our analyses further revealed that the genomes of these LUSC patients are chromosomally unstable, which leads us to believe that such non-actionable genomic rearrangements may be a result of “chromosomal chaos” most probably not representing exclusive cancer-driving genes in this cancer entity. We emphasise that caution should be taken when novel fusions are found and that the appearance of new gene fusions should always be interpreted in the molecular context of the respective disease.