Global patterns of mutational profiles in biliary tract cancer.

Biliary tract cancers (BTCs) are a group of rare but highly lethal malignancies that include intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder carcinoma (GBC). A major challenge in modeling and treating these cancers is their highly heterogeneous mutational landscapes, both within and across subtypes, as well as across geographic and etiological contexts. This heterogeneity necessitates large cohorts to enable robust statistical analyses. Here, we collate and analyze data from more than 30 next-generation sequencing studies to provide a comprehensive overview of BTC mutational patterns and their potential clinical implications. Mutation data from 5,123 BTC samples from 13 countries were standardized, focusing on a set of 29 bona fide oncogenes and tumor suppressor genes. We performed statistical analyses to evaluate hypotheses related to mutation prevalence, etiology, co-mutation patterns, and recurrent mutations. This analysis provides robust estimates of mutation prevalence across geographic regions, BTC subtypes, and hepatitis status, highlighting genes whose alteration frequencies vary by anatomical location and etiology. or example, iCCA in Eastern vs. Western hemispheres showed large differences in alteration prevalence for FGFR2, IDH1, KRAS, TP53, CDKN2A, and BAP1, whereas eCCA and GBC exhibited only modest hemispheric differences. We further show that these differences, as well as those observed between iCCA and eCCA, are partly explained by variation in the mutation profiles and prevalences of small- vs. large-duct subtypes. The large sample size also enabled systematic characterization of gene-gene co-occurrence and mutual exclusivity across BTC subtypes, along with a clinically oriented catalogue of recurrent mutations in oncogenes and tumor suppressor genes. This integrative cross-study analysis provides a global view of BTC genomics, clarifying how geography, etiology, and anatomical subtype collectively shape driver mutation landscapes. Our results provide statistical depth, uncover new mutational relationships, and suggest high-priority avenues for basic and translational research in biliary tract cancer. By integrating data across diverse geographic and etiological contexts, this study highlights how mutation prevalence and co-mutation patterns vary systematically with anatomical subtype, hepatitis status, and region. These findings offer a more nuanced framework for interpreting BTC genomics and underscore the importance of stratified approaches to research and treatment. Collectively, this work establishes a robust foundation for future biological studies, biomarker development, and the design of clinical trials that are tailored to geographic origin, underlying etiology, and specific mutational and co-mutation landscapes, ultimately supporting more precise and effective therapeutic strategies in BTC.