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Identification of Sleeping Beauty Transposon Insertions in Solid Tumors using Linker-mediated PCR
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A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes

Jorge de la Rosa1,2,3, Julia Weber4,5, Mathias Josef Friedrich1

  • 1The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

Nature Genetics
|March 21, 2017
PubMed

Insights

This study identifies new tumor suppressor genes that cooperate with PTEN to prevent cancer. These findings reveal complex tumor suppressor networks with potential clinical applications in various cancer types.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Cancer genome sequencing reveals numerous genetic alterations, necessitating methods to understand their functional significance.
  • Identifying genes that cooperate with tumor suppressors like PTEN is crucial for understanding cancer development.

Purpose of the Study:

  • To discover novel Pten-cooperating tumor suppressors using a whole-body insertional mutagenesis screen in mice.
  • To identify and validate new tumor suppressor genes involved in prostate, breast, and skin cancers.

Main Methods:

  • Developed a novel whole-body insertional mutagenesis screen in mice by coupling a Sleeping Beauty transposon to Pten disruption.
  • Analyzed 278 transposition-induced tumors across multiple cancer types.
  • Validated candidate genes through in vitro and in vivo experiments.

Main Results:

  • Identified tissue-specific and shared gene sets involved in cancer, including ZBTB20, CELF2, PARD3, AKAP13, and WAC.
  • Validated these genes as novel tumor suppressors cooperating with PTEN in prostate cancer, demonstrating synergy in preventing invasion.
  • Showed obligate haploinsufficiency of Wac in a Pten-deficient context.

Conclusions:

  • Discovered complex PTEN-cooperating tumor suppressor networks across different cancer types.
  • Validated several novel tumor suppressor genes with potential clinical relevance.
  • Highlighted the role of WAC in autophagy regulation within a Pten-deficient cancer context.

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