Integration of Gene Dosage and Gene Expression in Non-Small Cell Lung Cancer, Identification of HSP90 as Potential Target

• Published in: PloS one Vol. 3; no. 3; p. e0001722
• Main Authors: Gallegos Ruiz, Mariëlle I., Floor, Karijn, Roepman, Paul, Rodriguez, José A., Meijer, Gerrit A., Mooi, Wolter J., Jassem, Ewa, Niklinski, Jacek, Muley, Thomas, van Zandwijk, Nico, Smit, Egbert F., Beebe, Kristin, Neckers, Len, Ylstra, Bauke, Giaccone, Giuseppe
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.03.2008; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - secondary; Algorithms; Cancer; Cancer genetics; Carcinoma, Large Cell - genetics; Carcinoma, Large Cell - metabolism; Carcinoma, Large Cell - secondary; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - secondary; Cell cycle; Chromosome Aberrations; Chromosome deletion; Chromosomes, Human, Pair 14 - genetics; Clonal deletion; Comparative analysis; Copy number; Cytogenetics; Deoxyribonucleic acid; DNA; DNA microarrays; Drug dosages; Endocrinology; Epidermal growth factor; Female; Follow-Up Studies; Gene deletion; Gene Dosage; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetics and Genomics; Genome, Human; Genomes; Genomics; Health aspects; Heat shock proteins; HSP90 Heat-Shock Proteins - genetics; Hsp90 protein; Humans; Hybridization; Immunology; Kinases; Lung cancer; Lung diseases; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Male; Medical research; Medical treatment; Mutation; Neoplasm Staging; Non-small cell lung cancer; Non-small cell lung carcinoma; Oligonucleotide Array Sequence Analysis; Oncology; Oncology/Lung Cancer; Pathology; Patients; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal transduction; Small cell lung cancer; Survival; Survival Rate; Thyroid cancer; Tumor Cells, Cultured; Tumorigenesis; Tumors; United States > US; Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0001722

Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC) represents 85% of all lung cancers. Understanding the molecular events in non-small cell lung cancer (NSCLC) is essential to improve early diagnosis and treatment for this disease. In an attempt 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 14q32.2-33 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 with 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. We suggest that targeting HSP90 will have clinical impact for NSCLC patients.