title: Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor.
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.
  
  
  CONCLUSIONS
  This study identifies many novel candidate genetic drivers of lung cancer and demonstrates that CUL3 acts as a tumor suppressor by regulating oxidative stress.
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Minneapolis Medical Research Foundation, Minneapolis, Minnesota.
authors.forename: Casey
authors.initials: C
authors.lastname: Dorr
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Callie
authors.initials: C
authors.lastname: Janik
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Madison
authors.initials: M
authors.lastname: Weg
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Department of Comparative and Molecular Biosciences, University of Minnesota, St. Paul, Minnesota.
authors.forename: Raha A
authors.initials: RA
authors.lastname: Been
authors.affiliation: Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Justin
authors.initials: J
authors.lastname: Bader
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Ryan
authors.initials: R
authors.lastname: Kang
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Brandon
authors.initials: B
authors.lastname: Ng
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Foran
authors.affiliation: Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Landman
authors.affiliation: Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota. Comparative Pathology Shared Resource, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michael
authors.initials: M
authors.lastname: Steinbach
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.affiliation: Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Kevin A T
authors.initials: KA
authors.lastname: Silverstein
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Department of Genetic, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Department of Genetic, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota. star0044@umn.edu.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Starr
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D044842:Cullin Proteins / Q000235:genetics*; D004251:DNA Transposable Elements; D005260:Female; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016296:Mutagenesis; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: C503645:CUL3 protein, human; C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D004251:DNA Transposable Elements