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".