34 Gene fusions in 1,015 human cancer cell lines: integrating large-scale genomic data, high-throughput drug and CRISPR/Cas9 screens to assess functional relevance and therapeutic potential

Introduction Translating our understanding of genetic alterations in cancer into clinical care remains a major challenge. The discovery of gene fusions such as EML4-ALK in lung cancer and BCR-ABL1 in chronic myeloid leukaemia have already led to changes in clinical care. Advances in next-generation sequencing have accelerated the rate at which novel gene fusions are discovered, but important questions remain about their roles in promoting oncogenic phenotypes and their relevance in drug response. Here, we combine RNA sequencing, CRISPR/Cas9 screens and high-throughput drug sensitivity data in a panel of 1000 human cancer cell lines to examine the occurrence and functional relevance of gene fusions in cancer. Material and methods We performed RNA-sequencing on 1015 human cancer cell lines, representing 42 cancer types. We called fusions using three algorithms: TopHat Fusion, DeFuse and RNA-STAR fusion. Further, we integrate high-throughput drug screening data across >350 compounds, single-nucleotide variants, copy number variation, gene expression data and genome-wide CRISPR/Cas9 dropout screening data to systematically search for gene fusions with functional relevance. Results and discussions We find 8546 distinct gene fusion events across our panel of cell lines. These include well understood gene fusions (e.g. ALK -fusions, BCR-ABL1 and EWSR1-FLI1 ), as well as novel fusions that involve known cancer driver genes. We are able to recapitulate previously identified gene fusion-drug response associations using an unguided statistical analysis. Furthermore, we developed a systematic unguided approach of using CRISPR/Cas9 gene essentiality data to identify essential gene fusions. This approach recapitulates known essential gene fusions and provides evidence for the oncogenic relevance for previously poorly understood gene fusions. Conclusion In this study, we provide an annotation of gene fusions in 1015 human cancer cell lines. Our systematic analysis of the functional role of gene fusions captures the oncogenic and therapeutic relevance of known gene fusions, and highlights potential therapeutic opportunities of previously uncharacterised gene fusions.