Therapeutic vulnerabilities in CCA from different etiologies identified using integrative multi-omics enhancer activity profiling

Through integrative analysis of enhancer and transcriptomic landscapes of CCA from diverse populations, we identified 3 distinct groups, associated with different etiologies, that were enriched in unique pathways. The first group (ESTRO) displayed aberrant enhancer activation in estrogen signaling, and were comprised of mostly fluke-associated CCAs. Another group (OXPHO) displayed activated oxidative phosphorylation pathways, and were associated with hypermethylated BAP1 and IDH-mutant CCAs. Immune-related pathways were activated in the final group (IMMUN), made up of an immunogenic CCA subtype as well as CCA with aristolochic acid mutational signatures. Drug inhibitors of identified enriched pathways reduced tumor growth in in vitro and in vivo models.EGA study EGAS00001007309