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

Gallegos Ruiz MI, Floor K, Roepman P, Rodriguez JA, Meijer GA, Mooi WJ, Jassem E, Niklinski J, Muley T, van Zandwijk N, Smit EF, Beebe K, Neckers L, Ylstra B, Giaccone G - PLoS ONE (2008)

Bottom Line: Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC) represents 85% of all lung cancers.An integrative analysis tool was applied to determine whether chromosomal copy number affects gene expression.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands.

ABSTRACT

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.

Methodology and principal findings: 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.

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Related in: MedlinePlus

Percentage of called gains and losses and their effect on gene expression in 32 NSCLC patients.Summary plot for called gains and losses in 32 resected NSCLC patients with DNA copy number changes indicated in grey. Positive values indicate the percentage of samples found with a gain. Negative values indicate the percentage of samples harboring a loss at the specified chromosome location. Genes in specified regions affected by copy number gain are indicated in green and genes affected by copy number loss are indicated in red. A selection of affected genes is indicated. The full list of 359 affected transcripts can be found in supplementary table S1.
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pone-0001722-g001: Percentage of called gains and losses and their effect on gene expression in 32 NSCLC patients.Summary plot for called gains and losses in 32 resected NSCLC patients with DNA copy number changes indicated in grey. Positive values indicate the percentage of samples found with a gain. Negative values indicate the percentage of samples harboring a loss at the specified chromosome location. Genes in specified regions affected by copy number gain are indicated in green and genes affected by copy number loss are indicated in red. A selection of affected genes is indicated. The full list of 359 affected transcripts can be found in supplementary table S1.

Mentions: Chromosomal aberrations were abundant in the 32 NSCLC patients analyzed. In order to identify breakpoints of gains and losses we applied the algorithm CGH call [11]. In Table 2 the chromosomal regions in which gains or losses were present in at least 20% of patients are listed. The statistical tool ACE-it [6] was used to determine whether gene copy number affected gene expression. A total of 359 transcripts turned out to be significantly affected by copy number. In Figure 1 the areas of affected genes are indicated for 32 NSCLC patients, shown in green (gained regions) or red (lost regions).


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

Gallegos Ruiz MI, Floor K, Roepman P, Rodriguez JA, Meijer GA, Mooi WJ, Jassem E, Niklinski J, Muley T, van Zandwijk N, Smit EF, Beebe K, Neckers L, Ylstra B, Giaccone G - PLoS ONE (2008)

Percentage of called gains and losses and their effect on gene expression in 32 NSCLC patients.Summary plot for called gains and losses in 32 resected NSCLC patients with DNA copy number changes indicated in grey. Positive values indicate the percentage of samples found with a gain. Negative values indicate the percentage of samples harboring a loss at the specified chromosome location. Genes in specified regions affected by copy number gain are indicated in green and genes affected by copy number loss are indicated in red. A selection of affected genes is indicated. The full list of 359 affected transcripts can be found in supplementary table S1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2254495&req=5

pone-0001722-g001: Percentage of called gains and losses and their effect on gene expression in 32 NSCLC patients.Summary plot for called gains and losses in 32 resected NSCLC patients with DNA copy number changes indicated in grey. Positive values indicate the percentage of samples found with a gain. Negative values indicate the percentage of samples harboring a loss at the specified chromosome location. Genes in specified regions affected by copy number gain are indicated in green and genes affected by copy number loss are indicated in red. A selection of affected genes is indicated. The full list of 359 affected transcripts can be found in supplementary table S1.
Mentions: Chromosomal aberrations were abundant in the 32 NSCLC patients analyzed. In order to identify breakpoints of gains and losses we applied the algorithm CGH call [11]. In Table 2 the chromosomal regions in which gains or losses were present in at least 20% of patients are listed. The statistical tool ACE-it [6] was used to determine whether gene copy number affected gene expression. A total of 359 transcripts turned out to be significantly affected by copy number. In Figure 1 the areas of affected genes are indicated for 32 NSCLC patients, shown in green (gained regions) or red (lost regions).

Bottom Line: Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC) represents 85% of all lung cancers.An integrative analysis tool was applied to determine whether chromosomal copy number affects gene expression.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands.

ABSTRACT

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.

Methodology and principal findings: 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.

Show MeSH
Related in: MedlinePlus