A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes

Nat Genet. 2017 May;49(5):730-741. doi: 10.1038/ng.3817. Epub 2017 Mar 20.

Abstract

The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer. We validated ZBTB20, CELF2, PARD3, AKAP13 and WAC, which were identified by our screens in multiple cancer types, as new tumor suppressor genes in prostate cancer. We demonstrated their synergy with PTEN in preventing invasion in vitro and confirmed their clinical relevance. Further characterization of Wac in vivo showed obligate haploinsufficiency for this gene (which encodes an autophagy-regulating factor) in a Pten-deficient context. Our study identified complex PTEN-cooperating tumor suppressor networks in different cancer types, with potential clinical implications.

MeSH terms

  • Animals
  • Cell Line
  • Cell Movement / genetics
  • DNA Transposable Elements / genetics*
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Gene Dosage
  • Genes, Tumor Suppressor*
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mice, Knockout
  • Mice, Transgenic
  • Mutagenesis, Insertional*
  • Mutation
  • PTEN Phosphohydrolase / genetics*
  • Prostate / cytology
  • Prostate / metabolism
  • Prostatic Neoplasms / genetics*
  • RNA Interference
  • Signal Transduction / genetics

Substances

  • DNA Transposable Elements
  • PTEN Phosphohydrolase
  • Pten protein, mouse