Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor

Mol Cancer Res. 2015 Aug;13(8):1238-47. doi: 10.1158/1541-7786.MCR-14-0674-T. Epub 2015 May 20.

Abstract

Non-small cell lung cancers (NSCLC) harbor thousands of passenger events that hide genetic drivers. Even highly recurrent events in NSCLC, such as mutations in PTEN, EGFR, KRAS, and ALK, are detected, at most, in only 30% of patients. Thus, many unidentified low-penetrant events are causing a significant portion of lung cancers. To detect low-penetrance drivers of NSCLC, a forward genetic screen was performed in mice using the Sleeping Beauty (SB) DNA transposon as a random mutagen to generate lung tumors in a Pten-deficient background. SB mutations coupled with Pten deficiency were sufficient to produce lung tumors in 29% of mice. Pten deficiency alone, without SB mutations, resulted in lung tumors in 11% of mice, whereas the rate in control mice was approximately 3%. In addition, thyroid cancer and other carcinomas, as well as the presence of bronchiolar and alveolar epithelialization, in mice deficient for Pten were also identified. Analysis of common transposon insertion sites identified 76 candidate cancer driver genes. These genes are frequently dysregulated in human lung cancers and implicate several signaling pathways. Cullin3 (Cul3), a member of a ubiquitin ligase complex that plays a role in the oxidative stress response pathway, was identified in the screen and evidence demonstrates that Cul3 functions as a tumor suppressor.

Implications: This study identifies many novel candidate genetic drivers of lung cancer and demonstrates that CUL3 acts as a tumor suppressor by regulating oxidative stress.

Publication types

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

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cullin Proteins / genetics*
  • DNA Transposable Elements*
  • Female
  • Genes, Tumor Suppressor*
  • HEK293 Cells
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutagenesis*
  • Mutation
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Oxidative Stress
  • Signal Transduction

Substances

  • CUL3 protein, human
  • Cul3 protein, mouse
  • Cullin Proteins
  • DNA Transposable Elements