Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer

Josef Horak; Ondrej Kubecek; Anna Siskova; Katerina Honkova; Irena Chvojkova; Marketa Krupova; Monika Manethova; Sona Vodenkova; Sandra García-Mulero; Stanislav John; Filip Cecka; Ludmila Vodickova; Jiri Petera; Stanislav Filip; Veronika Vymetalkova

doi:10.3389/fonc.2023.1133598

Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer

Front Oncol. 2023 Apr 27:13:1133598. doi: 10.3389/fonc.2023.1133598. eCollection 2023.

Authors

Josef Horak^{1

2}, Ondrej Kubecek³, Anna Siskova^{1

4}, Katerina Honkova⁵, Irena Chvojkova⁵, Marketa Krupova⁶, Monika Manethova⁶, Sona Vodenkova^{1

7}, Sandra García-Mulero^{8

9}, Stanislav John³, Filip Cecka¹⁰, Ludmila Vodickova^{1

4

7}, Jiri Petera³, Stanislav Filip³, Veronika Vymetalkova^{1

4

7}

Affiliations

¹ Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.
² Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czechia.
³ Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia.
⁴ Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czechia.
⁵ Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.
⁶ The Fingerland Department of Pathology, University Hospital in Hradec Kralove, Hradec Kralove, Czechia.
⁷ Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia.
⁸ Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO)-Oncobell Programme, Bellvitge Biomedical Research Institute Oncobell Programme, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
⁹ Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Oncobell Programme, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
¹⁰ Department of Surgery, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, Czechia.

Abstract

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.

Keywords: MiRNAome; colorectal cancer; liver metastasis; methylome; transcriptome.

Grants and funding

This project was supported by the Czech health research council of the Ministry of Health of the Czech Republic (NV19–09-00237), by the Cooperatio Program, research area, Oncology and Haematology”, Cooperatio No. 43 -Surgical Disciplines, and by the National Operation Programme: National Institute for Cancer Research LX22NPO05102. The methylation part was funded by the Ministry of Education, Youth and Sports of the Czech Republic (Research Infrastructure NanoEnviCZ, LM2018124) and The European Union - European Structural and Investments Funds in the frame of Operational Programme Research Development and Education - project Pro-NanoEnviCz (Project No. CZ.02.1.01/0.0/0.0/16_013/0001821).