Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability

Genomic instabilityis a hallmark of human cancer, and results in widespread somatic copynumber alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations ( copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS( Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosomecomponents were the most prevalent. One of these, the pre-mRNA splicing factorSF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPSgene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copynumber from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency.