Identification of prognostically-relevant signature genes differentially expressed between primary colorectal carcinoma and hepatic metastasis

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4116 Background: Colorectal cancer (CRC) is the third most common cancer in the US. Hepatic metastasis (HM), the most common distant metastasis from CRC and occurring in about 60% of CRC patients during the course of their treatment, is a significant clinical problem. Although several clinical prognostic factors for HM from CRC have been identified, little is known about its molecular aspect. Methods: Under IRB approved protocols, we profiled gene expression in a set of 30 specimens from primary CRC and 31 unmatched specimens of HM from CRC. To survey the molecular variations between the two groups, we used cDNA microarrays containing ∼22,000 human genes, and identified differentially expressed genes using the Significance Analysis of Microarrays (SAM) method. To further characterize the clinical relevance of differentially expressed genes, we used immunohistochemistry (IHC) on tissue microarrays of tumor tissues obtained from an independent dataset of 154 patients with primary CRC. Results: Supervised analysis using SAM identified >200 genes with significantly higher expression in HM from CRC compared to primary CRC (and also compared to normal liver), with a false discovery rate (FDR) of <1%. IHC staining of two highly ranked differentially expressed signature genes, SPP1 (osteopontin) and LEF1 (lymphoid enhancer factor-1; a transcriptional mediator of Wnt pathway activation), showed protein overexpression (OE) in 60% and 44% of CRC cases, respectively; with a significant correlation with liver involvement in LEF1 expression (chi-square p=0.04) vs. SPP1 OE (p=0.14). Kaplan Meier analysis revealed significantly worsening survival in patients with LEF1 OE (p<0.01), but not SPP1 (p=0.14). Multivariate analysis identified several relevant prognostic markers: stage (p<0.001), nodal status (p <0.01) and LEF1 OE (p=0.02). Conclusions: Among signature genes differentially expressed between CRC and HM, we demonstrate LEF1, not SPP1, OE to be a poor prognostic factor for survival. Further studies are needed to characterize other signature genes, and to refine our understanding of the role of altered LEF1 expression in CRC tumorigenesis. No significant financial relationships to disclose.