LAUSR

Background and Aims: Primary liver cancers (LCs), including HCC and intrahepatic cholangiocarcinoma (iCCA), are derived from a common developmental lineage, conferring a molecular spectrum between them. To elucidate the molecular spectrum, we performed an integrative analysis of transcriptome profiles associated with patients’ radiopathologic features. Approach and Results: We identified four LC subtypes (LC1–LC4) from RNA‐sequencing profiles, revealing intermediate subtypes between HCC and iCCA. LC1 is a typical HCC characterized by active bile acid metabolism, telomerase reverse transcriptase promoter mutations, and high uptake of gadoxetic acid in MRI. LC2 is an iCCA‐like HCC characterized by expression of the progenitor cell–like trait, tumor protein p53 mutations, and rim arterial‐phase hyperenhancement in MRI. LC3 is an HCC‐like iCCA, mainly small duct (SD) type, associated with HCC‐related etiologic factors. LC4 is further subclassified into LC4‐SD and LC4‐large duct iCCAs according to the pathological features, which exhibited distinct genetic variations (e.g., KRAS, isocitrate dehydrogenase 1/2 mutation, and FGF receptor 2 fusion), stromal type, and prognostic outcomes. Conclusions: Our integrated view of the molecular spectrum of LCs can identify subtypes associated with transcriptomic, genomic, and radiopathologic features, providing mechanistic insights into heterogeneous LC progression.