Multi-omics characterization of cholangiocarcinoma and association with prognostic and therapeutic molecular subtypes.

60 Background: Cholangiocarcinoma (CCA) is a highly heterogeneous cancer with a poor prognosis. Previous multiplex profiling have been partly identified molecular features of CCA but the underpinnings of CCA’s development, tumor microenvironment (TME) and therapeutic resistance remain largely unknown. Our objective was to characterise genomic/transcriptomic/epigenetic landscapes of CCA aiming to establish therapeutic associated molecular classification. Methods: We profiled 450 untreated CCA with various anatomical subtypes from multiple centers with whole-genome sequencing (WGS), whole-exome sequencing (WES), RNA sequencing, whole-genome bisulfite sequencing (WGBS) and protein immunohistochemistry and performed an integrated analysis as well as clinical-pathological characteristics to identify the molecular determinants, developing a classifier for clinical-molecular prognostic classification and predicting responsiveness of immune checkpoint blockade therapy. Results: Integrative clustering defined 4 CCA subtypes (C1-C4) with distinct clinical-pathological features, TME characteristics, putative therapeutics and prognoses. Then, a 160-gene classifier was created, and this classifier was able to classify the vast majority of CCA cases into the C1-C4 subtypes and was verified to be valuable for guiding clinical treatment. Patients with C3 characteristics had the best prognosis and exhibited higher responsiveness to immune checkpoint blockade therapy than others (75% vs 15%). Moreover, we demonstrated that the CpG island methylator phenotype (CIMP) could serve as an indicator of immunocyte infiltration in the TME of CCA. SOS1 and ATP2B1 were identified as potential new driver genes and significant prognostic biomarkers of CCA. Conclusions: Our studies yield insights into the heterogeneity and clinical-molecular classification of CCA and could aid in the establishment of diagnostic and individualized therapeutic strategies.