Despite distant metastases being the critical factor affecting patients' survival, they remain poorly understood. Our study thus aimed to molecularly characterize colorectal cancer liver metastases (CRCLMs) and explore whether molecular profiles differ between Synchronous (SmCRC) and Metachronous (MmCRC) colorectal cancer. This characterization was performed by whole exome sequencing, whole transcriptome, whole methylome, and miRNAome. The most frequent somatic mutations were in APC, SYNE1, TP53, and TTN genes. Among the differently methylated and expressed genes were those involved in cell adhesion, extracellular matrix organization and degradation, neuroactive ligand-receptor interaction. The top up-regulated microRNAs were hsa-miR-135b-3p and -5p, and the hsa-miR-200-family while the hsa-miR-548-family belonged to the top down-regulated. MmCRC patients evinced higher tumor mutational burden, a wider median of duplications and deletions, and a heterogeneous mutational signature than SmCRC. Regarding chronicity, a significant down-regulation of SMOC2 and PPP1R9A genes in SmCRC compared to MmCRC was observed. Two miRNAs were deregulated between SmCRC and MmCRC, hsa-miR-625-3p and has-miR-1269-3p. The combined data identified the IPO5 gene. Regardless of miRNA expression levels, the combined analysis resulted in 107 deregulated genes related to relaxin, estrogen, PI3K-Akt, WNT signaling pathways, and intracellular second messenger signaling. The intersection between our and validation sets confirmed the validity of our results. We have identified genes and pathways that may be considered as actionable targets in CRCLMs. Our data also provide a valuable resource for understanding molecular distinctions between SmCRC and MmCRC. They have the potential to enhance the diagnosis, prognostication, and management of CRCLMs by a molecularly targeted approach.

Biomedical Centre Faculty of Medicine in Pilsen Charles University Pilsen Czechia

Department of Genetic Toxicology and Epigenetics Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czechia

Department of Medical Genetics 3rd Faculty of Medicine Charles University Prague Czechia

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czechia

Department of Oncology and Radiotherapy Faculty of Medicine and University Hospital in Hradec Kralove Charles University Hradec Kralove Czechia

Department of Surgery Faculty of Medicine and University Hospital in Hradec Kralove Charles University Hradec Kralove Czechia

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czechia

Program in Molecular Mechanisms and Experimental Therapy in Oncology Hospitalet de Llobregat Barcelona Spain

The Fingerland Department of Pathology University Hospital in Hradec Kralove Hradec Kralove Czechia

Unit of Biomarkers and Susceptibility Oncology Data Analytics Program Hospitalet de Llobregat Barcelona Spain

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