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

Elife. 2017 Feb 8;6:e23268. doi: 10.7554/eLife.23268.

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 SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number 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.

Keywords: CYCLOPS genes; Cancer therapeutics; Copy number alterations; SF3B1; Spliceosome; Target identification and validation; cancer biology; human; human biology; medicine; mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Gene Dosage*
  • Humans
  • Neoplasms / genetics*
  • Neoplasms / pathology*
  • Phosphoproteins / genetics*
  • RNA Splicing Factors / genetics*

Substances

  • Phosphoproteins
  • RNA Splicing Factors
  • SF3B1 protein, human