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

• DOI: 10.1158/1541-7786.c.6540763.v1
• Publication Date: 2024-03-12T16:15:45Z
• Authors: Casey Dorr; Callie Janik; Madison Weg; Raha A. Been; Justin Bader; Ryan Kang; Brandon Ng; Lindsey Foran; Sean R. Landman; M. Gerard O'Sullivan; Michael Steinbach; Aaron L. Sarver; Kevin A.T. Silver...; David A. Largaespada; Timothy K. Starr

<div>Abstract<p>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 <i>PTEN</i>, <i>EGFR</i>, <i>KRAS</i>, and <i>ALK</i>, 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 <i>Pten</i>-deficient background. SB mutations coupled with <i>Pten</i> deficiency were sufficient to produce lung tumors in 29% of mice. <i>Pten</i> 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 <i>Pten</i> 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. <i>Cullin3</i> (<i>Cul3</i>), 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 <i>Cul3</i> functions as a tumor suppressor.</p><p><b>Implications:</b> This study identifies many novel candidate genetic drivers of lung cancer and demonstrates that <i>CUL3</i> acts as a tumor suppressor by regulating oxidative stress. <i>Mol Cancer Res; 13(8); 1238–47. ©2015 AACR</i>.</p></div>