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


RESULTS
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.


CONCLUSIONS
We suggest that targeting HSP90 will have clinical impact for NSCLC patients.
Gallegos Ruiz
Mariëlle I
MI
Department of Medical Oncology, Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands.
Floor
Karijn
K
Roepman
Paul
P
Rodriguez
José A
JA
Meijer
Gerrit A
GA
Mooi
Wolter J
WJ
Jassem
Ewa
E
Niklinski
Jacek
J
Muley
Thomas
T
van Zandwijk
Nico
N
Smit
Egbert F
EF
Beebe
Kristin
K
Neckers
Len
L
Ylstra
Bauke
B
Giaccone
Giuseppe
G
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D002869:Chromosome Aberrations; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D008297:Male; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D018841:HSP90 Heat-Shock Proteins; D012333:RNA, Messenger