Primary Colorectal Tumor Displays Differential Genomic Expression Profiles Associated with Hepatic and Peritoneal Metastases

SIMPLE SUMMARY: Metastatic spread is the main prognostic factor in patients with colorectal cancer (CRC). We investigated the preferential metastatic spread of CRC toward two prevalent and clinically relevant metastatic sites, liver and peritoneum. By comparing the differential gene expression profile of primary tumors with isolated liver or peritoneal metastases, we identified a 61-gene signature associated with a specific metastatic route. Primary CRC tumors expressing the peritoneal signature were characterized by epithelial mesenchymal transition and apical epithelial junction activation but also an implication of stem cell signaling pathway. We identified specific clinico-pathological correlations and prognostic impacts of liver and peritoneal signatures in a TCGA dataset. As a future perspective, biomarkers identified in the primary tumor may contribute to improved risk stratification for individualized patient follow-up and to identify new therapeutic targets for a precision-based approach. ABSTRACT: Background: Despite improvements in characterization of CRC heterogeneity, appropriate risk stratification tools are still lacking in clinical practice. This study aimed to elucidate the primary tumor transcriptomic signatures associated with distinct metastatic routes. Methods: Primary tumor specimens obtained from CRC patients with either isolated LM (CRC-Liver) or PM (CRC-Peritoneum) were analyzed by transcriptomic mRNA sequencing, gene set enrichment analyses (GSEA) and immunohistochemistry. We further assessed the clinico-pathological associations and prognostic value of our signature in the COAD-TCGA independent cohort. Results: We identified a significantly different distribution of Consensus Molecular Subtypes between CRC-Liver and CRC-peritoneum groups. A transcriptomic signature based on 61 genes discriminated between liver and peritoneal metastatic routes. GSEA showed a higher expression of immune response and epithelial invasion pathways in CRC-Peritoneum samples and activation of proliferation and metabolic pathways in CRC-Liver samples. The biological relevance of RNA-Seq results was validated by the immunohistochemical expression of three significantly differentially expressed genes (ACE2, CLDN18 and DUSP4) in our signature. In silico analysis of the COAD-TCGA showed that the CRC-Peritoneum signature was associated with negative prognostic factors and poor overall and disease-free survivals. Conclusions: CRC primary tumors spreading to the liver and peritoneum display significantly different transcriptomic profiles. The implementation of this signature in clinical practice could contribute to identify new therapeutic targets for stage IV CRC and to define individualized follow-up programs in stage II-III CRC.