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

Abstract

Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number 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 spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor <i>SF3B1</i>, is also frequently mutated in cancer. We validated <i>SF3B1</i> as a CYCLOPS gene and found that human cancer cells harboring partial <i>SF3B1</i> copy-loss lack a reservoir of SF3b complex that protects cells with normal <i>SF3B1</i> copy number from cell death upon partial <i>SF3B1</i> suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type <i>SF3B1</i> as a novel, non-driver cancer gene dependency.