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  P2.03 - Biology (ID 162)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Biology
  • Presentations: 1
  • Now Available
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 30805

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    P2.03-24 - Concurrent Aberrations in G2/M-Phase Transcriptional Programs and Genomic Gatekeepers Highlight Lung Cancer Predisposition in COPD Patients (Now Available) (ID 2665)

    10:15 - 18:15  |  Author(s): Raymond T Ng
    • Abstract
    • Slides

    Background
    

    Chronic obstructive pulmonary disease (COPD) is associated with a 7-fold increased risk of lung cancer occurrence. COPD is defined by clinical symptoms and lung function measurement. It is characterized by chronic inflammation, small airway remodelling and loss as well as destruction of alveoli (emphysema). While an important lung cancer risk factor, the molecular overlap between COPD and lung cancer tumorigenesis is relatively understudied.

    Method
    

    In order to examine the commonalities between these two diseases, we first analyzed small airway epithelial gene expression profiles from 127 COPD and 140 non-COPD ever-smoker patients obtained by bronchial brushing. We performed weighted gene correlation network analysis (WGCNA) on these gene expression profiles to discover deregulated gene modules (‘metagenes’) associated with reduced lung function (Forced Expiratory Volume at 1 second, FEV₁)—a clinical measure of COPD severity most robustly negatively correlated with lung cancer risk. We then assessed the preservation of these modules in two non-small cell lung cancer (NSCLC) tumour/normal data sets (lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), n= 887 tumors total). Airway and tumor patient cohorts were matched for age, gender, tumour stage, and smoking status.

    Result
    

    We discovered 10 distinct small airway expression modules, two of which were significantly negatively correlated (p < 0.05) with patient FEV₁. One of these FEV₁ modules was the top overall module preserved in both NSCLC subtypes. This lung cancer-FEV₁ module contained 31 genes solely enriched for two related mitotic functions— G2/M phase transition (BH-p = 0.02) and mitotic roles of polo-like kinase (BH-p = 0.001, n=31). Of these, 28 genes were significantly overexpressed in both LUAD and LUSC, and mapped to a highly-clustered sub-network of 23 proteins with 465 known and in silico predicted protein-protein interactions. When tumours enriched for this lung-cancer-FEV₁ gene signature were further examined, we observed a significant co-occurrence of DNA-level alterations in DNA damage associated checkpoints, specifically mutated TP53.

    Conclusion
    

    Coordinated gene expression changes associated with COPD severity measures in small airways and preserved in NSCLC tumors are enriched for G2/M phase transition genes. These genes are further disrupted in tumors, where co-occurring mutations to gate-keeper genes occur. Progression of mitosis during abnormal aneuploidy in lung tissues of COPD patients may confer increased risk of oncogenic transformation in this population, and may underlie the molecular link between COPD and lung cancer.

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