Novel Molecular Subgroups of Intrahepatic Cholangiocarcinoma Discovered by Single-Cell RNA Sequencing-Assisted Multi-Omics Analysis

ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but highly aggressive tumour type that responds poorly to chemotherapy and immunotherapy. Comprehensive molecular characterization of ICC is essential for the development of novel therapeutics. Here, we constructed two independent cohorts from two clinic centres. A comprehensive multiomics analysis of ICC via proteomic, whole-exon sequencing (WES) and single-cell RNA sequencing (scRNA-seq) was performed. Novel ICC tumour subtypes were derived in the training cohort (n = 110) using proteomic signatures and their associated activated pathways, which was further validated in the validation cohort (n = 41). Three molecular subtypes, chromatin remodelling, metabolism, and chronic inflammation, with distinct prognoses in ICC were identified. The chronic inflammation subtype was associated with a poor prognosis. Our random forest algorithm revealed that the mutation of KMT2D frequently occurred in the metabolism subtype and was associated with lower inflammatory activity. scRNA-seq further identified an APOE+C1QB+ macrophage subtype, which showed the capacity to reshape the chronic inflammation subtype and contribute to a poor prognosis in ICC. Altogether, with single-cell transcriptome-assisted multiomics analysis, we identified novel molecular subtypes of ICC and validated APOE+C1QB+ TAMs as potential immunotherapy targets against ICC.

ORGANISM(S): Homo Sapiens

SUBMITTER: Tiannan Guo  

PROVIDER: PXD033206 | iProX | Wed Apr 13 00:00:00 BST 2022

REPOSITORIES: iProX