Gene Fusions Create Partner And Collateral Dependencies That Are Essential To Cancer Cell Survival.

Abstract Gene fusions frequently result from rearrangements in cancer genomes. In many instances, they play an important role in oncogenesis; in other instances, they are thought to be passenger events. Regulatory element rearrangements and copy number alterations resulting from these structural variants (SVs) lead to transcriptional dysregulation across cancers, though the extent to which these events result in functional dependencies with an impact on cancer cell survival is variable. We demonstrated enrichment of fusion partner genes and “collateral genes”, or genes in the same topologically associating domains (TADs) as fusion partners, among CRISPR-Cas9 dependencies across 209 cell lines with whole-genome sequencing data. We subsequently used CRISPR-Cas9 dependency screens to evaluate the fitness impact of 3,277 fusions across 645 cell lines with RNAseq data from the Cancer Dependency Map (DepMap). We found that 35% of cell lines harbored either a fusion partner dependency or a collateral dependency. CRISPR-Cas9 loss-of-function screening identified fusion-associated dependencies in 20 of 35 (57%) COSMIC fusions from our dataset. Fusion-associated dependencies revealed numerous novel oncogenic drivers and clinically translatable alterations. We observed several instances of intrachromosomal FOXR1 fusions associated with FOXR1 as a strong dependency, occurring independently in osteosarcoma, lung adenocarcinoma, and bladder carcinoma cell lines; these dependencies were validated through in vitro CRISPR-Cas9 knockout. FOXR1 fusions leading to FOXR1 overexpression were seen in an independent cohort of clinical tumor samples, speaking to the clinical relevance of this finding. FGFR3, a targetable kinase, was the key dependency in t(4;14) multiple myeloma cells that harbored an IgH-NSD2 fusion. We also showed that the implications of fusion-associated dependencies extended beyond two-dimensional cell line space, exemplified by dependency on EML4 in the context of a THADA-MTA3 fusion persisting in spheroid models. Broadly, fusions can result in partner and collateral dependencies that have biological and clinical relevance across cancer types. Citation Format: Riaz Gillani, Bo Kyung A. Seong, Jett Crowdis, Jake R. Conway, Neekesh V. Dharia, Saif Alimohamed, Brian J. Haas, Kyuho Han, Jihye Park, David Liu, Felix Dietlein, Meng Xiao He, Alma Imamovic, Clement Ma, Michael C. Bassik, Jesse S. Boehm, Francisca Vazquez, Alexander Gusev, Katherine A. Janeway, James M. McFarland, Kimberly Stegmaier, Eliezer M. Van Allen. Gene fusions create partner and collateral dependencies that are essential to cancer cell survival [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 96.