Data from DNA Copy-Number Alterations Underlie Gene Expression Differences between Microsatellite Stable and Unstable Colorectal Cancers

Abstract

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.

Authors 14

1. Robert N. Jorissen

   Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research

   Affiliation as printed

   Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research;

2. Lara Rachel Lipton

   Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research

   Affiliation as printed

   Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research;

3. Peter Gibbs

   Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research

   Affiliation as printed

   Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research;

4. Jayesh Desai

   Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research

   Affiliation as printed

   Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research;

5. Ian T. Jones

   The Royal Melbourne Hospital

   Affiliation as printed

   Department of Colorectal Surgery, Royal Melbourne Hospital, Parkville,Victoria, Australia;

6. Timothy Joseph Yeatman

   Moffitt Cancer Center

   Affiliation as printed

   Department of Surgery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida;

7. Philip East
   Affiliation as printed

   Computational Genome Analysis Laboratory and

8. Ian P. M. Tomlinson

   University of London · Queen Mary University of London · Cancer Research UK · Barts Cancer Institute

   Affiliation as printed

   Institute of Cancer, Bart's and the London Medical School, Queen Mary College, University of London, London, United Kingdom;

   Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK;

9. Hein W. Verspaget Aachen Department of Gastroenterology and Hepatology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Gastroenterology and Hepatology, Leiden University Medical Centre, The Netherlands ;

10. Lauri A. Aaltonen

    University of Helsinki · Medical Genetics Center

    Affiliation as printed

    Department of Medical Genetics, Biomedicum,

    University of Helsinki, Helsinki, Finland;

11. Mogens Kruhøffer

    Aarhus University Hospital

    Affiliation as printed

    Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Denmark

12. Torben Falck Orntoft

    Aarhus University Hospital

    Affiliation as printed

    Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Denmark

13. Claus L. Andersen

    Aarhus University Hospital

    Affiliation as printed

    Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Denmark

14. Oliver M. Sieber corresponding

    Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research · Ludwig Cancer Research

    Affiliation as printed

    Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research;