Abstract
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.
Highlights
Non-small cell lung cancer (NSCLC) represents a morphologically and clinically heterogeneous cancer type, with overall poor prognosis [1]
This study provides a genome-wide analysis of gene copy number changes and corresponding gene expression levels in 190 NSCLC patients
Typical examples, where high copy number gain correlates with high gene expression are MBIP, Cullin-Associated And Neddylation-Dissociated 1 (CAND1), TBL1XR1 and RABP1B. (2) Higher correlation coefficients were associated with higher copy number and expression levels
Summary
NSCLC represents a morphologically and clinically heterogeneous cancer type, with overall poor prognosis [1]. A well-known example is HER2 amplification in breast [11,12] and gastric cancer [13], which translates into higher gene and protein expression and define distinct biological subgroups in these cancers. Such relations have been described in NSCLC [8, 14,15,16,17,18,19]. A genome-wide analysis of gene copy number and corresponding gene expression was performed in a clinically well-characterized NSCLC patient cohort
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