Author of

• 18272

  +

  P3.01 - Poster Session with Presenters Present (ID 469)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 18324

    +

    P3.01-052 - DNA Adductomics to Identify the Role of Inflammation in NNK-Induced Lung Carcinogenesis (ID 6027)

    14:30 - 14:30  |  Author(s): R. Dator
    • Abstract

    Background:
    The association between pulmonary inflammation and lung cancer is well established. Smokers with chronic obstructive pulmonary disease (COPD) have higher risk of developing lung cancer than smokers without this condition. However, the molecular events underlying the association between inflammation and cancer in the lung are poorly understood. To better understand this association, an A/J mouse model was recently developed which combines exposure to the tobacco specific lung carcinogen NNK and the pro-inflammatory agent LPS. Using an innovative mass spectrometry based DNA adductomic approach, we plan to measure the DNA damage resulting from these exposures in this model.
    
    Methods:
    Both NNK and LPS can induce DNA modifications (DNA adducts), if not eliminated or repaired these adducts can result in miscoding events that can lead to misregulation of normal cellular growth control mechanisms and ultimately may result in cancer formation. Traditionally, the standard LC-MS methodology used for DNA adduct measurement focuses on the investigation of small numbers of anticipated DNA adducts based on a priori assumptions regarding their formation from specific exposures or chemicals. This approach does not account for the complexity of in vivo DNA adduct formation resulting from endogenous sources such as oxidative stress, lipid peroxidation or aberrant metabolism, or as a result of exposure to complex mixtures of chemicals which cannot be completely anticipated or predicted. To address this limitation, we have developed a high resolution/accurate mass data dependent-constant neutral loss-MS[3] methodology for DNA adductomics using ion trap-orbital trap technology to screen for all DNA modifications simultaneously.
    
    Results:
    We have successfully tested our method on mixtures of standards and applied it to lung DNA samples collected from mice exposed to NNK and to LPS. Our method allowed for the detection of the expected DNA adducts resulting from NNK as well as a number of endogenous DNA adducts resulting from lipid peroxidation, oxidative stress and aberrant metabolism resulting from the LPS induced inflammatory process.
    
    Conclusion:
    These results confirm the ability of our DNA adductomic approach to characterize the DNA damage deriving from these exposures. Our comprehensive DNA adductomic approach contributes to the development of new tools needed to investigate lung carcinogenesis, to elucidate its mechanisms and dissect the molecular pathways involved in inflammation-driven lung cancer, with the ultimate goal of identifying preventive and therapeutic strategies.