Molecular Differences between Hepatic and Extrahepatic Metastases from Left-Sided and Right-Sided Colorectal Cancer: Potential Metastatic and Prognostic Biomarkers

Background: The most significant prognostic variables for colorectal cancer (CRC) are tumor sidedness and patterns of metastatic spread. However, less is known about the differences in the mutational profile of hepatic and extrahepatic metastases between left-sided and right-sided colorectal cancer. To address this knowledge gap, we sought to analyze the association between different metastatic sites and the gene mutational profiles in each population. We aimed to discover the molecular heterogeneity between these two subtypes of colorectal cancer.Methods: We retrospectively analyzed mutations from 185 colorectal cancer patients. The samples for next generation sequencing were primary colon tumor tissues. Formalin-fixed, paraffin-embedded tumor tissues were collected and deep sequencing targeting 1021 genes was conducted to analyze genomic alteration. Correlation analysis was performed by Chi-square or Fisher's exact tests.Results: A total of 185 CRC patients (132 left-sided colon cancer (LCC) and 53 right-sided colon cancer (RCC)) were analyzed. These included 60 patients with (32.4%) solitary liver metastasis (SLM) cohort, 43 patients (23.2%) with multiple liver metastases (MLM) cohort, 56 patients (30.3%) with extrahepatic metastases (EHM) cohort, and 26 patients (14.1%) without metastases (control cohort). Tumor protein 53 (TP53, 88% vs. 68%, p < 0.05) and adenomatous polyposis coli (APC, 78% vs. 58%, p < 0.05) were found to be mutated more frequently in LCC than RCC. In contrast, B-raf murine sarcoma viral oncogene homologue B (BRAF, 5% vs. 11%, p < 0.05), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA, 13% vs. 23%, p < 0.05), lysine demethylase 6A (KDM6A, 1% vs. 8%, p < 0.05), FAT atypical cadherin 2 (FAT2, 2% vs. 11%, p < 0.05), and SRY-box transcription factor 9 (SOX9, 7% vs. 19%, p < 0.05) were more common in RCC patients compared with those with LCC. In LCC, APC was more frequently mutated in SLM, MLM, and control cohorts than in the EHM cohort (85% vs. 83% vs. 90% vs. 57%, p < 0.05). In RCC, the mutation frequencies of APC and PIK3CA were more significant in the SLM cohort when compared to the EHM cohort. However, a converse result was observed for the SMAD family member 4 (SMAD4) gene.Conclusions: These results demonstrate the molecular heterogeneity between hepatic and extrahepatic metastases from left- and right-sided colorectal cancer. These findings could help us better understand the mechanisms underlying tumor metastasis and reveal disparities in survival among metastatic locations.