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: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 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): A. Niculescu-Mizil
    • 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).