Author of

• 17398

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  P2.01 - Poster Session with Presenters Present (ID 461)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 17439

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    P2.01-041 - Integrated Proteo-Genomics Analyses Reveal Extensive Tumor Heterogeneity and Novel Somatic Variants in Lung Adenocarcinoma (ID 6082)

    14:30 - 14:30  |  Author(s): S. Gao
    • Abstract

    Background:
    Tumor heterogeneity is a major impediment to targeted treatment response in a variety of cancers, including lung cancer, the commonest cause of cancer death. However, the extent of heterogeneity at the genomic and proteomic level along with its effects on treatment response may be patient-specific.
    
    Methods:
    We undertook comprehensive whole genome, exome or targeted sequencing, together with mass spectrometry-based proteomics analyses on twelve sequentially procured lung and lymph node metastatic sites and normal blood from an African American never-smoker lung adenocarcinoma patient who had survived with metastatic disease for over seven years while being treated with single or combination ERBB2-directed therapies.
    
    Results:
    Surprisingly, only 1% of somatic variants were common between the two sites, as revealed by WGS. Interestingly, one novel somatic translocation, PLAG1-ACTA2 was identified in both sites resulting in overexpression of ACTA2 that may have been the driver of early metastasis in this patient. The likely predominant driver of proliferation, ERBB2, was focally amplified along with CDK12, greater in the lung compared to the lymph nodes. However, an ERBB2 L869R mutation was specific to the lymph node. We also discovered a novel CDK12 G879V mutation that was specific to the lung. Isogenic MCF10A cells expressing ERBB2 L869R were more proliferative than those expressing wild type ERBB2. Cells expressing ERBB2 L869R that developed lapatinib resistance showed a mesenchymal phenotype, increased migration, and produced significantly more lung metastases than lapatinib-sensitive ERBB2 wild-type cells in a tail-vein injection assay, implicating this mutation in repeated progression of lymph node metastases. The CDK12 mutation is expected to have resulted in a non-functional kinase, lower expression of DNA damage response genes, greater instability of the lung tumor genome, and increased sensitivity to chemotherapy. Accordingly, there was no metastatic sites evident at autopsy in the lung, suggesting the lung metastatic sites were essentially cured. We further sought to correlate the genomic heterogeneity with alterations in the proteome and phosphoproteome using high-resolution mass spectrometry. For this purpose, we first assembled patient-specific database including all somatic variants, as revealed by WGS, from the lung and lymph node to interrogate the mass spectrometry data. Several aspects of the genomic heterogeneity were evident at the protein-level. These include the identification of the mutant CDK12 G879V peptide and higher expression of ERBB2 in the lung.
    
    Conclusion:
    The integrated proteo-genomics analyses reveal unprecedented tumor heterogeneity in a patient with lung adenocarcinoma. However, similarities in key tumor driver pathways remain.