Author of

• 15382

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  P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

  • Event: WCLC 2015
  • Type: Poster
  • Track: Biology, Pathology, and Molecular Testing
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)

  • 15421

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    P3.04-039 - Characterization of RNA Splicing Factor Mutations in Lung Adenocarcinoma (ID 2949)

    09:30 - 09:30  |  Author(s): A.N. Brooks
    • Abstract
    • Slides

    Background:
    Large-scale genomic surveys of lung adenocarcinoma have revealed unexpected mutations in RNA splicing factors such as U2AF1 and RBM10, and it remains unknown how changes in splicing are involved in promoting cancer. Somatic alterations in the RNA-binding protein RBM10 occur at a frequency of approximately 7% and consist predominantly of loss-of-function mutations. In this study, we sought to investigate the functional impact of RBM10 mutations in lung cancer.
    
    Methods:
    RBM10 mutant non-small cell lung cancer (NSCLC) cell lines were identified by analysis of Cancer Cell Line Encyclopedia gene expression data and Sanger sequencing of RBM10 coding exons. Ectopic expression of wildtype RBM10 or a control protein (BFP) was induced using the tetracycline-regulatory system. RNA–sequencing and JuncBASE software were used to identify differentially spliced transcripts between RBM10 wildtype and mutant cells. Changes in individual splicing events were validated by RT-PCR.
    
    Results:
    We have identified several NSCLC cell lines harboring loss-of-function mutations in RBM10. Restoring expression of wildtype RBM10 in these RBM10-mutant cell lines resulted in significant growth suppression and inhibition of anchorage-independent growth. These phenotypic effects were associated with a variety of splicing changes and expression of wildtype RBM10 frequently increased skipping of cassette exons. Expression of RBM10 variants with either deletion of an RNA recognition motif (RRM), or containing a cancer-associated missense mutation in the RRM, were significantly diminished in their ability to promote exon skipping and suppress cellular proliferation.
    
    Conclusion:
    Our results suggest that RBM10 functions as a novel tumor suppressor in lung adenocarcinoma through its effects on RNA splicing. Further work is needed to better understand how changes in specific splicing events may be directly contributing to lung tumorigenesis.
    
    

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