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T. Tokar
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-015 - Differentially Expressed microRNAs in Lung Adenocarcinoma Invert Effects of Copy Number Aberrations of Prognostic Genes (ID 4771)
14:30 - 14:30 | Author(s): T. Tokar
- Abstract
Background:
Across multiple cancer histologies, many significantly down-regulated genes reside within chromosomal regions with increased number of copies, and vice versa. These “paradoxical genes” have been usually ignored as a noise, but could be a consequence of epigenetic regulatory mechanisms, including microRNA-mediated control of mRNA transcription.
Methods:
To identify paradoxical genes in lung adenocarcinoma (LUAD) we curated and analyzed gene expression and copy number aberrations across 1,064 LUAD samples, including newly-generated aCGH data from 65 samples. We then analyzed 9 LUAD microRNA expression studies to compile a list of consistently deregulated microRNAs. Finally, using microRNA:gene networks from mirDIP we examined possible association between microRNAs and paradoxical genes.
Results:
We identified 85 genes whose differential expression consistently contrasts the aberrations of their copy numbers. 70 genes were validated using TCGA-LUAD data. We showed that paradoxical expression of these genes is associated with 19 microRNAs, whose significant deregulation in LUAD has been consistently reported. Importantly, these genes form a clinically significant prognostic signature.Figure 1Figure 2
Conclusion:
Paradoxical gene expression, caused by microRNA deregulation, is preserved across patient cohorts, and forms a prognostic LUAD signature.
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P2.01-037 - Molecular Biology Underlying COPD and Lung Cancer Converge on FOXM1 Network (ID 5773)
14:30 - 14:30 | Author(s): T. Tokar
- Abstract
Background:
Chronic obstructive pulmonary disease (COPD) is a progressive, inflammatory lung disease associated with an up to 10-fold increased risk of lung cancer (LC). COPD and LC share common etiologies including genetic susceptibilities and risk factors, such as smoking. This study systematically characterizes the molecular overlap between COPD and LC.
Methods:
Small airway gene expression data was obtained from subjects with spirometry measures (n=267) (GSE37147). Genome-wide, multi-omics data for lung adenocarcinoma (LUAD) tumor and non-malignant lung tissues from two cohorts (TCGA, n=515; BCCA, n=90) was analyzed. Weighted correlation network analysis (WGCNA) was applied to identify clusters (modules) of highly correlated genes across airway expression profiles. Combined module expression (eigengene scores) were used to: 1) identify modules negatively associated with FEV~1~ and 2) calculate module preservation in lung tumors. Signaling network, pathway and gene ontology analyses were performed using IID, pathDIP, ClueGo and PARADIGM. Known and predicted protein-protein physical interactions (PPIs) were obtained from IID. Network analysis and visualization was performed in NAViGaTOR.
Results:
A module of 31 genes significantly co-expressed across small airways was negatively associated with FEV~1~ and preserved in LUAD tumors. Genes in this module were enriched in functions associated with cell cycle progression, and known and/or predicted to physically interact in the protein complex critical to mediating G2/M progression. The forkhead transcription factor FOXM1 network was the most highly perturbed entity across 515 LUAD tumors. FOXM1 is an essential mitotic protein, known to regulate expression of genes involved in cell cycle progression, as well as stress response to ROS and DNA damage, angiogenesis and metastasis. COPD-related airway mRNA changes and genes highly altered at the DNA and mRNA level in LUAD tumors directly converge on the FOXM1 regulated mitotic complex proteins and/or FOXM1 transcription factor network.
Conclusion:
FOXM1 is overexpressed in multiple cancer types where it is correlated with poor prognosis and oncogenic transformation of epithelia through induction of genomic instability. The convergence of COPD and LUAD changes on this network may underlie increased LC risk in COPD patients, warranting further exploration as a target for COPD treatment and/or LC prevention or treatment.
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-019 - Desmoplasia is Associated with Poor Prognosis and Carcinoma-Associated Fibroblast Heterogeneity in Non-Small Cell Lung Cancer (ID 5281)
14:30 - 14:30 | Author(s): T. Tokar
- Abstract
Background:
Cancer-associated fibroblasts (CAFs) are known to influence tumor development, progression and metastasis. Their characteristics and prognostic role in non-small cell lung cancer (NSCLC) patients have been recognized. However, the functional heterogeneity of CAFs between patients and its genetic basis is less understood.
Methods:
Two pathologists scored for desmoplasia on Hematoxylin-Eosin stained sections of resected lung tumors from two patient cohorts: one consisting of 171 NSCLC patients (128 adenocarcinoma, 43 squamous carcinoma) and the second of 24 primary cultures of CAFs. Percent area of desmoplasia among total tumor stroma was used to define high desmoplasia (HD) versus low desmoplasia (LD). The desmoplasia and survival analysis were assessed for 171 NSCLC patients. Gene expression data on RNA extracted from CAFs in contracted gels following 24 hours incubation was obtained using Illumina Human HT-12v4 Bead Chips array and was preprocessed and normalized using RMA and values were log2 transformed. Significant genes whose expression is strongly correlated (Spearman correlation coefficient and p value) with percent of desmoplasia were identified in both cohorts. The gene set enrichment analysis (GSEA) was applied to test for the enrichment of CAF cohort significant genes in 171 NSCLC cohort. Additionally, CAF significant genes were subjected to pathway enrichment analysis using Pathway Data Integration Portal ver. 2.5 (http://ophid.utoronto.ca/pahtDIP).
Results:
The prognosis of adenocarcinoma patients with HD had poorer outcome in comparison to the patients with LD (disease free survival at 3 years 34% vs. 75% p=0.00045 and relapse rate 41% vs. 14%, p=0.0051). In the CAF cohort, the number of genes that are significantly associated with desmoplasia for enrichment are 356. Using GSEA, these genes were enriched in 171 NSCLC cohort (with a p value of 0.045). Protein-protein interaction (PPI) partners of these 356 genes were acquired using Integrated Interaction Database – IID (version 2016-03, http://dcv.uhnres.utoronto.ca/iid/). Obtained genes were then ranked according to their degree, i.e., number of PPIs. Top 44 (top 1%) of the genes were then selected to pathway enrichment analysis using pathDIP version 2.5. 245 pathways that significantly enriched by these 44 genes (FDR < 0.01) were obtained. Many of these pathways are known to be involved in lung cancer.
Conclusion:
We demonstrated that the prognosis of lung adenocarcinoma patients with HD had poorer outcome in comparison to the patients with LD. Furthermore, PPI analysis of CAF genes associated with HD reveals enrichment of many cancer-related pathways, suggesting their high relevance to lung cancer.
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P3.01-051 - Analysis of Molecular Aberrations Associated with COPD in Patients with Lung Cancer (ID 5220)
14:30 - 14:30 | Author(s): T. Tokar
- Abstract
Background:
Chronic obstructive pulmonary disease (COPD) is serious lung disease that is often associated with development of lung cancer. It is well known that both diseases share many common risk factors, most prominently smoking. Much less is known about molecular link between these two pathologies. How to predict which COPD patients will develop lung cancer? Can COPD drugs reduce or increase lung cancer risk?
Methods:
To answer these question we analyzed molecular data from tumour and normal tissue samples obtained from 72 lung cancer patients, comprising methylation, copy number aberrations, gene expression and microRNA expression data acquired from each sample. Various matching spirometric parameters, were used as indicator of severity of the airflow limitation in patients with COPD and were evaluated as potential prognostic indicators with respect to survival. We studied molecular aberrations to identify those that correlate with these parameters or differ between COPD and non-COPD patients. Using data from Broad Institute's Connectivity Map (CMAP), we analyzed gene expression effects of various pharmacological compounds, to identify potential benefits/hazards in administration of various drugs (and their combinations) typically used for treatment of COPD and/or lung cancer, with respect to prognosis of patients with COPD vs. those without COPD.
Results:
We identified group of 619 genes and 20 microRNAs whose expression is significantly associated with patient's COPD status (and severity of the disease). COPD-associated genes significantly enrich pathways related to G2 M phase of the cell cycle, G-protein coupled receptors signalling, Rho GTPases signalling and several cancer-related pathways. We found that subset of these genes constitute prognostic signature that was subsequently validated using independent publicly available dataset (HR = 2.66, p = 0.01, N = 204, GSE31210). We have also shown that alternative signature with similar prognostic power can also be constituted by COPD-associated micoRNAs (HR = 2.07, p = 0.036, N = 189, TCGA LUAD miRNAseq data). By subsequent CMAP analysis we then identified drugs that significantly (p < 0.01) affect expression of the COPD-associated genes in a manner that may improve the patients prognosis, and those that may cause its worsening. First mentioned include fenspiride – drug for obstructive airways disease and urological anti-infective phenazopyridine. Interestingly, we found calcium folinate - frequently used as a detoxifying agent for antineoplastic treatment, including treatment of lung cancer, as a potentially harmfull.
Conclusion:
Genes and microRNAs associated with COPD are significantly associated with prognosis of the lung cancer patients.
