DNA copy-number alterations underlie gene expression differences between microsatellite stable and unstable colorectal cancers.
DNA copy-number alterations underlie gene expression differences between microsatellite stable and unstable colorectal cancers.
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DOI：
10.1158/1078-0432.ccr-08-1431
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发表时间：
2008-12-15
期刊：
影响因子：
--
通讯作者：
Sieber OM
中科院分区：
文献类型：
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作者：
Jorissen RN;Lipton L;Gibbs P;Chapman M;Desai J;Jones IT;Yeatman TJ;East P;Tomlinson IP;Verspaget HW;Aaltonen LA;Kruhøffer M;Orntoft TF;Andersen CL;Sieber OM
About 15% of colorectal cancers (CRCs) harbor microsatellite instability (MSI). MSI-associated gene expression changes have been identified in CRCs, 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. DNA microarray data on 89 MSI and 140 MSS CRCs 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. MSI-associated gene expression changes in CRCs 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). Our results demonstrate cross-study consistency of MSI-associated gene expression changes in CRCs. DNA copy-number alterations partly cause the differences in gene expression between MSI and MSS cancers.
