Integrative analysis of genome-wide gene copy number changes and gene expression in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) represents a genomically unstable cancer type with extensive copy number aberrations. The relationship of gene copy number alterations and subsequent mRNA levels has only fragmentarily been described. The aim of this study was to conduct a genome-wide analysis of gene copy number gains and corresponding gene expression levels in a clinically well annotated NSCLC patient cohort (n = 190) and their association with survival. While more than half of all analyzed gene copy number-gene expression pairs showed statistically significant correlations (10,296 of 18,756 genes), high correlations, with a correlation coefficient >0.7, were obtained only in a subset of 301 genes (1.6%), including KRAS, EGFR and MDM2. Higher correlation coefficients were associated with higher copy number and expression levels. Strong correlations were frequently based on few tumors with high copy number gains and correspondingly increased mRNA expression. Among the highly correlating genes, GO groups associated with posttranslational protein modifications were particularly frequent, including ubiquitination and neddylation. In a meta-analysis including 1,779 patients we found that survival associated genes were overrepresented among highly correlating genes (61 of the 301 highly correlating genes, FDR adjusted p<0.05). Among them are the chaperone CCT2, the core complex protein NUP107 and the ubiquitination and neddylation associated protein CAND1. In conclusion, in a comprehensive analysis we described a distinct set of highly correlating genes. These genes were found to be overrepresented among survival-associated genes based on gene expression in a large collection of publicly available datasets.

An integrative analysis of the tumorigenic role of TAZ in human non-small cell lung cancer.

PURPOSE: TAZ, also known as WWTR1, has recently been suggested as an oncogene in non-small cell lung cancer (NSCLC). We investigated the clinical relevance of TAZ expression and its functional role in NSCLC tumorigenesis. EXPERIMENTAL DESIGN: We characterized TAZ at the DNA (n=192), mRNA (n=196), and protein levels (n=345) in an NSCLC patient cohort. Gene expression analysis was complemented by a meta-analysis of public datasets (n=1,382). The effects of TAZ on cell proliferation and cell cycle were analyzed in cell cultures and on tumor growth in mice. TAZ-dependent microarray-based expression profiles in NSCLC cells were combined with molecular profiles in human NSCLC tissues for in silico analysis. RESULTS: Higher TAZ mRNA and protein levels were associated with shorter patient survival. Transduction of TAZ enhanced cell proliferation and tumorigenesis in bronchial epithelial cells, whereas TAZ silencing suppressed cell proliferation and induced cell cycle arrest in NSCLC cells. Microarray and cell culture experiments showed that ErbB ligands (amphiregulin, epiregulin, and neuregulin 1) are downstream targets of TAZ. Our in silico analysis revealed a TAZ signature that substantiated the clinical impact of TAZ and confirmed its relationship to the epidermal growth factor receptor signaling pathway. CONCLUSION: TAZ expression defines a clinically distinct subgroup of patients with NSCLC. ErbB ligands are suggested to mediate the effects of TAZ on lung cancer progression. Our findings emphasize the tumorigenic role of TAZ and may serve as the basis for new treatment strategies.