Integrated co-mutation profiling reveals a novel genomic classification for prognostication and tailored therapy in biliary tract cancer

Biliary tract cancers (BTCs) exhibit substantial genomic heterogeneity, which is further compounded by the presence of co-mutations, thereby increasing therapeutic complexity. Utilizing a large discovery cohort of 2,378 patients and an independent immunochemotherapy (ICT) cohort of 59 patients, this study investigates the patterns of co-mutation in BTCs and their clinical implications. We identified co-mutation features with potential relevance for guiding targeted therapeutic strategies. Furthermore, we delineated deleterious co-mutations (DCMs) and deleterious single mutations (DSMs) associated with adverse clinical outcomes. By integrating DCMs and DSMs, we classified BTCs into three genomic subtypes: wild-type (WT), single-hit (SH), and multi-hit (MH). The MH subtype is characterized by a high co-mutation burden and specific mutational signatures. Despite having a high prevalence of microsatellite instability and abundant actionable alterations, this subtype shows a significantly worse response to ICT. It is also associated with shorter overall survival. In contrast, the WT subtype exhibits the best outcomes. Our findings provide a molecular framework for stratifying BTC patients. MH tumors might be prioritized for genotype-matched targeted therapy, although direct comparative evidence is still lacking.