Colorectal cancer (CRC) tumorigenesis is a complex process involving the accumulation of multiple genetic and epigenetic alterations. The loss of genomic stability, including chromosome instability (CIN) and microsatellite instability (MSI), is a key molecular event in cancer formation. Our understanding of the genomic alterations that lead to CRC has been based on the conventional CGH assays. What is unclear is if such genomic abnormalities are mirrored by alterations at the transcriptional level, and if so, could predict clinical outcome of CRC patients. We performed expression profiling on 156 CRC tumors and conducted clustering analysis to correlate gene expression with different types of genomic abnormalities. 24 out of 28 high-degree microsatellite instability (MSI-H) tumors were tightly clustered together, indicating distinct expression pattern of this specific group that are predominantly occurred in the proximal colon. Pathway analysis revealed that genes involved in differentiation, mucinous phenotype and lymphocytic infiltration constitute the signature cluster for MSI-H tumors. Many genes were mapped to chromosomal locations that are linked to genomic instabilities. An alternative clustering approach using filtered genes that are located on specific chromosome regions known to have genomic copy number changes revealed similar patterns for tumor subclasses. Such results indicate that changes on chromosomal level are mirrored by genetic changes at the gene expression level. The global gene expression change do not correlate with tumor progression and patient’s survival. Furthermore, patients with MSI-H tumors do not have a survival benefit over other patient subclasses in our analysis. Further analysis identified a set of genes whose expression was tightly associated with tumor progression and metastasis in concordance with Duke’s Staging. Univariate analysis using the Cox proportional hazards model led to identification of a subset of genes whose expression level was highly predictive of patient disease-free survival. The relevance of these genes with genomic instability will be discussed. Our study provides valuable insight that will aid in understanding carcinogenesis and progression of colorectal tumors, and the potential of utilizing such knowledge for disease management of CRC patients.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]