Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target

Abstract

Background: Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC) represent 85% of all lung canser. Understanding the molecular events in non-small cell lung cancer (NSLC) is essential to improve early diagnosis and treatment for this disease. Methodology and Principal Findings: In an attemp to identify novel NSCLC related genes, we performed a genome-wide screening of chromosomal copy number changes affecting gene expression using microarray based comparative genomic. hybridization and gene expression arrays on 32 radically resected tumor samples from stage I and II NSCLC patients. An integrative analysis tool was applied to determine whether chromosomal copy number affects gene expression. We identified a deletion on 14q32.33 as a common alteration in NSCLC (44%), which significantly influenced gene expression. for HSP90, residing on 14q32. This deletion was correlated with better overall survival (P = 0.008), survival was also longer in patients whose tumors had low expression levels of HSP90. We extended the analysis to three independent validation sets of NSCLC patients, and confirmed low HSP90 expression to be related longer overall survival (P = 0.003, P = 0.07 and P = 0.04). Furthermore, in vitro treatment with an HSP90 inhibitor had potent antiproliferative activity in NSCLC cell lines. Conclusion: We suggest that targeting HSP90 will have clinical for NSCLC patients. © 2008 Gallegos Ruiz et al.