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)

  • 15516

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    P3.04-134 - Cancer-Specific Production of N-Acetylaspartate via NAT8L Overexpression in Non-Small Cell Lung Cancer and its Potential as a Biomarker (ID 3570)

    09:30 - 09:30  |  Author(s): C. Lewis
    • Abstract

    Background:
    Lung cancer is the leading cause of cancer death worldwide, leading to 1.6 million deaths every year. The majority of lung cancer cases are diagnosed in late stages, and early-stage detection and treatment are now known to reduce mortality rates, as recently reported for non-invasive screening with low-dose CT (LDCT) scan. Currently, LDCT screening is recommended only for the high-risk population of smokers over 55 years of age. This limitation is due to high false positive rates (96.4%) as well as risks of radiation exposure in LDCT. For better screening methods, recent studies have attempted to use diverse biological fluid samples from patients for finding new lung cancer biomarkers. Unlike diagnostic biomarkers that are required to have high sensitivity for clinical application, screening biomarkers must have high specificity (i.e. low false positive rates) in order to avoid a large number of people without lung cancer from undergoing invasive or costly procedures for confirmation. Among recent studies on new lung cancer biomarkers, only one small-scale study identified a panel of blood microRNAs with cancer-specificity higher than 99%.
    
    Methods:
    In order to expedite the discovery of candidates for cancer-specific metabolites in lung cancer, we exploited a unique system of a non-small cell lung cancer (NSCLC) cell line and a line of immortalized bronchial epithelial cells derived from the same patient, HCC4017 and HBEC30KT, for the initial discovery. After molecular characterization, we validated the selected candidate’s cancer specificity in additional NSCLC cell lines and NSCLC tumors. The mechanistic basis of this cancer specificity was further investigated with NSCLC cell lines, and its clinical potential as a circulating biomarker of lung cancer was evaluated with selected blood samples from lung cancer patients.
    
    Results:
    Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N-acetylaspartate (NAA) in cancer cells ¾ undetectable in normal lung epithelium. NAA’s cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues. NAA’s cancer-specificity was further supported in our analysis of NAA synthetase (gene symbol: NAT8L) gene expression levels in The Cancer Genome Atlas: elevated NAT8L expression in approximately 40% of adenocarcinoma and squamous cell carcinoma cases (N=577), with minimal expression in all non-malignant lung tissues (N=74). We then showed that NAT8L is functionally involved in NAA production of NSCLC cells through siRNA-mediated suppression of NAT8L, which caused selective reduction of intracellular and secreted NAA. Our cell culture experiments also indicated that NAA biosynthesis in NSCLC cells depends on glutamine availability. For preliminary evaluation of NAA’s clinical potential as a circulating biomarker, we developed a sensitive NAA blood assay and found that NAA blood levels were elevated in approximately 40% of NSCLC patients (N=13) in comparison with age-matched healthy controls (N=21) among individuals aged 55 years or younger.
    
    Conclusion:
    Taken together, these results indicate that NAA is produced specifically in NSCLC tumors through NAT8L overexpression and its extracellular secretion can be detected in blood.