Deciphering human endogenous retrovirus expression in colorectal cancers: exploratory analysis regarding prognostic value in liver metastases

Background: Human Endogenous RetroVirus (HERV) expression in tumours reflects epigenetic dysregulation of cancer and an oncogenic factor through promoter/enhancer action on genes. While more than 50% of colorectal cancers develop liver metastases, HERV has not been studied in this context. Methods: We collected 400 RNA-seq samples from over 200 patients with primary and liver metastases, including public data and a novel set of 200 samples. Findings: We observed global stability of HERV expression between liver metastases and primary colorectal cancers, suggesting an early oncogenic footprint. We identified a list of 17 HERV loci for liver metastatic colorectal cancer (lmCRC) characterization; with tumour-specificity validated in single-cell metastatic colorectal cancer data and normal tissue bulk RNA-seq. Eleven loci produced HERV-derived peptides as per tandem mass spectrometry from primary colorectal cancer. Six loci were associated with the risk of relapse after lmCRC surgery. Four, HERVH_Xp22.32a, HERVH_20p11.23b, HERVH_13q33.3, HERVH_13q31.3, had adverse prognostic value (log-rank p-value 0.028, 0.0083, 9e-4, 0.05, respectively) while two, HERVH_Xp22.2c (log-rank p-value 0.032) and HERVH_8q21.3b (in multivariable models) were associated with better prognosis. Moreover, the markers showed a cumulative effect on survival when expressed. Some were associated with decreased cytotoxic immune cells and most of them correlated with cell cycle pathways. Interpretation: These findings provide insights into the lmCRC transcriptome landscape by suggesting prognostic markers and potential therapeutic targets. Funding: This work was supported by funding from institutional grants from Inserm, EFS, University of Bourgogne Franche-Comté, national found “ Agence Nationale de la Recherche – ANR-JCJC: Projet HERIC and ANR-22-CE45-0007”, and “ La ligue contre le cancer”.