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. 2008 Dec 15;14(24):8061-9.
doi: 10.1158/1078-0432.CCR-08-1431.

DNA copy-number alterations underlie gene expression differences between microsatellite stable and unstable colorectal cancers

Robert N Jorissen  1 , Lara Lipton, Peter Gibbs, Matthew Chapman, Jayesh Desai, Ian T Jones, Timothy J Yeatman, Philip East, Ian P M Tomlinson, Hein W Verspaget, Lauri A Aaltonen, Mogens Kruhøffer, Torben F Orntoft, Claus Lindbjerg Andersen, Oliver M Sieber
Affiliations

DNA copy-number alterations underlie gene expression differences between microsatellite stable and unstable colorectal cancers

Robert N Jorissen et al. Clin Cancer Res. .

Abstract

Purpose: About 15% of colorectal cancers harbor microsatellite instability (MSI). MSI-associated gene expression changes have been identified in colorectal cancers, but little overlap exists between signatures hindering an assessment of overall consistency. Little is known about the causes and downstream effects of differential gene expression.

Experimental design: DNA microarray data on 89 MSI and 140 microsatellite-stable (MSS) colorectal cancers from this study and 58 MSI and 77 MSS cases from three published reports were randomly divided into test and training sets. MSI-associated gene expression changes were assessed for cross-study consistency using training samples and validated as MSI classifier using test samples. Differences in biological pathways were identified by functional category analysis. Causation of differential gene expression was investigated by comparison to DNA copy-number data.

Results: MSI-associated gene expression changes in colorectal cancers were found to be highly consistent across multiple studies of primary tumors and cancer cell lines from patients of different ethnicities (P < 0.001). Clustering based on consistent changes separated additional test cases by MSI status, and classification of individual samples predicted MSI status with a sensitivity of 96% and specificity of 85%. Genes associated with immune response were up-regulated in MSI cancers, whereas genes associated with cell-cell adhesion, ion binding, and regulation of metabolism were down-regulated. Differential gene expression was shown to reflect systematic differences in DNA copy-number aberrations between MSI and MSS tumors (P < 0.001).

Conclusions: Our results show cross-study consistency of MSI-associated gene expression changes in colorectal cancers. DNA copy-number alterations partly cause the differences in gene expression between MSI and MSS cancers.

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Figures

Fig. 1
Fig. 1. Divisive hierarchical clustering of test colorectal cancers and cancer cell lines using the 829 and 192 consistent MSI-associated genes
A and B, primary CRCs clustered using the 829 and 192 gene sets, respectively. C, CRC cell lines clustered using the 192 gene (229 IMAGE clone) set. Samples are arranged along the x-axis and genes along the y-axis. Each square represents the expression level of a given gene in an individual sample. Red represents increased expression and green represents decreased expression relative to the mean-centered and scaled expression of the gene across the samples following quantile normalization across studies. Genes are grouped into those down-regulated (top) and those up-regulated (bottom) in MSI cases. For the dendrogram, orange lines represent MSI cases, blue lines MSS cases. Test samples included additional 30 MSI and 30 MSS cancers analyzed at the Aarhus University Hospital, 9 MSI and 15 MSS cancers from Watanabe et al (16), 11 MSI and 63 MSS cancers from the Royal Melbourne Hospital, and 5 MSI and 6 MSS CRC cell lines from Giacomini et al (17).
Fig. 2
Fig. 2. Comparison of DNA copy number and gene expression differences between matched MSI and MSS colorectal cancer cell lines and unmatched primary tumors
A and B, differential DNA copy-number and gene expression frequencies for 10 MSI and 13 MSS CRC cell lines; data from Douglas et al. (21) and Giacomini et al (17). C, differential DNA copy-number frequencies for 7 MSI and 102 MSS primary CRCs from Nakao et al (26). D, E, F and G, differential gene expression frequencies for 78 MSI and 77 MSS primary CRCs analyzed at Aarhus University Hospital, 11 MSI and 63 MSS primary CRCs analyzed at the Royal Melbourne Hospital, 33 MSI and 51 MSS primary CRCs from Watanabe et al (16), and 10 MSI and 10 MSS primary CRCs from Koinuma et al (13). For differential DNA copy number frequencies, lower bars represent losses or deletions, and the upper bars represent gains or amplifications. For differential gene expression frequencies, lower bars represent regions for which genes in MSS cases show predominant down-regulation, and the upper bars represent regions for which genes in MSS cases show predominant up-regulation. The dashed lines represent the location of the centromeres.
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