Enhancer RNAs profiling in colorectal cancer liver metastases reveals novel molecular subtypes with prognostic and therapeutic relevance.

BACKGROUND

Enhancer RNAs (eRNAs) are essential for cancer initiation and progression. However, the landscape of eRNAs and the clinical significance of eRNAs in colorectal cancer (CRC) liver metastases (CRLM) remain largely unknown.

METHODS

We comprehensively profiled eRNAs in a CRLM cohort and delineated eRNA-based CRLM subtypes through unsupervised clustering of eRNAs and validated the subtyping framework in an external cohort. Molecular characteristics, immune infiltration, prognostic outcomes, and chemotherapy responses of the novel CRLM subtypes were further explored. Finally, we explored chemoresistance-related eRNAs and tentatively investigated the roles of eRNAs in CRC oxaliplatin resistance in vitro.

RESULTS

Three novel eRNA-based CRLM subtypes, known as C1, C2, and C3, have been identified and validated in an external cohort. C1 has transcriptomic features of proliferative pathways. C2 is associated with the canonical primary CRC subtype. C3 is active in immune pathways and metabolic pathways. C2 has the highest chemotherapy response rate and has a better survival outcome than C1 and C3. In addition, we have revealed that knockdown of the eRNA (chr7:130571851-130572495) might influence oxaliplatin sensitivity in CRC cells.

CONCLUSIONS

Our findings unveil the molecular heterogeneity of CRLM through the lens of eRNAs and underscore the potential utility of eRNA in stratifying CRLM and guiding precision therapy.