Author of

• 11481

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  P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 2
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11495

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    P2.02-014 - Discovery of circulating protein biomarkers of lung dysplasia (ID 2481)

    13:11 - 13:28  |  Author(s): S. Williams
    • Abstract

    Background
    Endobronchial dysplasia is a premalignant lesion commonly found in current and former smokers. Identifying and treating these lesions before they progress to lung cancer may improve survival. The iloprost chemoprevention trial demonstrated that supplementation with the prostacyclin analog, iloprost, reduced histologic dysplasia in former smokers (Keith et al. Cancer Prev Res. 2011). However, accurate detection of dysplasia requires invasive bronchoscopy to collect multiple endobronchial biopsy samples. This study is the first step in generating blood-based markers of dysplasia to identify individuals at high risk for developing lung cancer and who could benefit from chemoprevention treatment.

    Methods
    Baseline serum samples (n=70) collected from current and former smokers enrolled in the iloprost chemoprevention trial were analyzed with the SOMAscan proteomic platform, which measures 1129 proteins with a median limit of detection of 40 fM and 5% CV. To characterize dysplasia, 6 standardized endobronchial sites, as well as any others that appeared suspicious by either white light or autofluorescence visualization, were biopsied from each study participant and scored by expert pathologists. Samples were stratified by worst biopsy score (Max) for proteomic analysis. Biomarkers correlating with Max pathology score were identified using principal component analysis (PCA), a multivariate technique to identify correlated variables, and the univariate, non-parametric Kolmogorov-Smirnov test (KS test). Serum proteins correlating with pulmonary function were also analyzed.

    Results
    Six proteins correlated with the progression of Max pathology. The change in serum level of these proteins ranged from 14-50% when comparing the lowest (n=16) and highest (n=39) Max pathology score groups. The proteins function in neoplastic progression, cell adhesion, inflammation and metabolic regulation. The protein with the most significant change (FDR correct p value = 0.05) regulates plasma clearance of steroid hormones. The serum protein most strongly correlated with lung function in our study was VEGFR2, which mediates VEGF induced endothelial proliferation and is known to be reduced in the lungs of smokers and patients with COPD and emphysema.

    Conclusion
    Our preliminary results of serum biomarkers associated with preneoplastic dysplasia warrant further study. If validated, this serum-based test to identify individuals who may benefit from chemopreventive intervention could impact lung cancer survival. This work was supported by NCI grants CA 58187 and CA165780.

  • 11496

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    P2.02-015 - Proteomic insights with lung cancer tumors based on histopathologic subtypes and genotypes (ID 2467)

    13:28 - 13:45  |  Author(s): S. Williams
    • Abstract

    Background
    Proteomic analysis of blood and tissue can reveal essential connections between the biochemical pathways altered in malignancy and tools for cancer diagnosis and treatment. The two major histologic subtypes of non-small cell lung cancer (NSCLC), adenocarcinoma (AD) and squamous cell carcinoma (SQ) differ in prognosis and optimal treatment. Targeting molecular pathways that drive malignancy has led to a paradigm shift in the development of specific treatments for patients based on their tumor mutation profile. We have conducted a comparative proteomic analysis of lung tumor histologic and driver mutation subsets to reveal biomarkers that link critical pathways for cell growth and survival to specific tumor phenotypes and genotypes.

    Methods
    We analyzed 68 NSCLC tumor and matched non-tumor tissue lysates (2 ug total protein/sample) with the SOMAscan proteomic platform, which measures 1129 proteins with a median limit of detection of 40 fM and 5% CV. The study consisted of 49 AD and 19 SQ tumors, 88% of which were Stage I or II. Somatic driver mutations were identified with multiplex PCR (SnapShot genotyping). Pairwise proteomic comparisons of tumor/non-tumor or AD/SQ tissue samples were performed using the Mann-Whitney test. The non-parametric Kruskal-Wallis test was used to discover differences among multiple pairwise driver mutation comparisons. Dependency network analysis was used to explore correlations enriched in tumor tissue vs non-tumor tissue. The statistical significance of the results was adjusted for multiple comparisons using false discovery rate (FDR) correction.

    Results
    Differences between tumor and non-tumor tissue were dominated by inflammatory, apoptotic and cell proliferation proteins. A total of 79 proteins were significantly different between AD and SQ at a 15% FDR. When compared to non-tumor levels, these proteins divided into 3 phenotypes: AD only (9 proteins), SQ only (19 proteins) or Both (51 proteins). Both refers to proteins that are tumor biomarkers in both AD and SQ and the protein levels are different between AD and SQ. The most common pattern was a progression in protein levels from non-tumor to AD to SQ, whether the pattern was higher or lower in tumor tissue. These proteins are members of cell proliferation and inflammatory pathways. This observation is consistent with the SQ only proteins, which are enriched for angiogenesis, cell proliferation and cell adhesion proteins. Driver mutation analysis revealed 5 inflammatory proteins that were higher in KRAS vs EGFR mutations and a TNF-alpha antagonist that was suppressed in EGFR mutants.

    Conclusion
    Unexpected findings that the AD proteome is closer to non-tumor lung tissue than SQ were revealed through broad proteomic profiling. Alteration in cell proliferation and inflammation pathways discovered in this study may lead to new insights in tumor biology and targeted therapeutics. This work was supported by a grant from the LUNGevity Foundation, NCI grant CA 58187 and Cancer Center Support Grant (P30CA046934).