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)

  • 15481

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    P3.04-099 - Proteome Signatures with Prognostic Impact Distinguish Non-Small Cell Lung Cancer Histology Subtypes and Metabolic States (ID 1009)

    09:30 - 09:30  |  Author(s): S. Sakashita
    • Abstract

    Background:
    We showed that the ability to establish a primary tumor­derived xenograft (PDX) is an independent predictor of shorter disease-free survival in early stage non-small cell lung carcinoma (NSCLC). Hence, NSCLC engraftment may select for critical, aggressive aspects of the cancer phenotype linked to disease progression. More recently we reported dramatic remodeling of NSCLC proteomes not predicted by genomics analyses, and which distinguish between the major histological subtypes of NSCLC. Herein we report details on NSCLC proteome remodeling as a major determinant of the expression of the metabolism proteome, engraftment, and related to patient outcome.
    
    Methods:
    Omics platforms were used to comprehensively characterize the genomes and proteomes of non-engrafting, engrafting, and derived PDX tumors associated with NSCLC. To facilitate proteome quantification by mass spectrometry, tumor samples were spiked with stable-isotope-labeled proteomes from a mixture of representative NSCLC cell lines as an internal standard.
    
    Results:
    Proteome remodeling in NSCLC is extensive and largely unpredicted by gene copy number variation, and not highly correlated with mRNA-based expression. Analysis of the proteomes of cognate engrafting primary and PDX tumor pairs revealed signatures comprising sets of metabolism proteins that distinguished between the major histological subtypes, and which were particularly highly recapitulated in PDX tumors. Interrogation of The Cancer Genome Atlas showed that the genes encoding the highly recapitulated metabolism protein signatures are for the most part not highly mutated in cancers. However, when the signature-encoding genes are considered as a singular polygene, then patients with mutations are recognized as having significantly different overall survival compared to patients without mutations. The proteomes of non-engrafting NSCLC tumors were generally more similar to normal lung than were engrafting tumor proteomes. Hence, proteome remodeling affects metabolic states associated with NSCLC outcome.
    
    Conclusion:
    NSCLC is characterized by significant proteome remodeling that is invisible to genomics platforms. The proteomes of engrafting and non-engrafting NSCLC primary tumors are different, suggesting the potential to develop proteome signatures as prognostic biomarkers. Moreover, proteome signatures associated with PDX engraftment and poor outcome may be a source of new drivers and targets in NSCLC.