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E.A. Vucic
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-091 - Concurrent Aberrations in G2/M-Phase Transcriptional Programs and Genomic Gatekeepers Highlight Lung Cancer Predisposition in COPD Patients (ID 8485)
09:30 - 09:30 | Author(s): E.A. Vucic
- Abstract
Background:
Patients with chronic obstructive pulmonary disease (COPD) have a 7-fold increased risk of developing lung cancer. COPD is defined by clinical symptoms and reduced lung function measurements. It is characterized by chronic inflammation, small airway remodelling and loss as well as destruction of alveoli (emphysema). While this disease is an important lung cancer risk factor independent of smoking, the molecular progression from COPD to lung cancer tumourigenesis is relatively understudied.
Method:
In order to examine the molecular overlap between these two diseases, we first analyzed small airway epithelial gene expression profiles obtained from bronchial brushings from 127 COPD and 140 non-COPD ever-smoker patients. 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, FEV~1~)—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 gene expression modules, two of which were significantly negatively correlated (p < 0.05) with patient FEV~1~. One of these FEV~1~ modules was the top overall module preserved in both NSCLC subtypes. This lung cancer-FEV~1~ 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-FEV~1 ~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 gatekeeper genes are present. 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 progression from COPD to lung cancer.
