Comparative analysis of genomic profiles and clinical outcomes in cholangiocarcinoma and gallbladder cancer

Cholangiocarcinoma (CCA) and gallbladder cancer (GBC) exhibit distinct biological behaviors and treatment responses, potentially driven by differences in their genomic landscapes. However, genomic investigations of biliary tract carcinoma (BTC) remain limited. A retrospective analysis was performed on next-generation sequencing data from 258 patients with BTC (188 with CCA, 70 with GBC), with an external cohort from Memorial Sloan-Kettering Cancer Center (MSKCC cohort) included for comparison. The most frequently altered genes in BTC included TP53 (56.6%), KRAS (27.9%), CDKN2A (21.3%), TERT (17.8%), and MCL1 (14.3%). CCA was predominantly characterized by mutations in ARID1A (15.4% vs. 5.7%, P = 0.04) and PBRM1 (10.1% vs. 0%, P = 0.003), as well as MCL1 amplifications (17.0% vs. 5.7%, P = 0.03), while GBC showed higher frequencies of TP53 alterations (78.6% vs. 47.9%, P < 0.001), ARID2 (15.7% vs. 3.7%, P = 0.002), TERT (24.3% vs. 11.2%, P = 0.02), CCNE1 amplifications (21.4% vs. 2.7%, P < 0.001), and SOX2 amplifications (4.3% vs. 0%, P = 0.02). GBC also exhibited an enrichment of alterations in the DNA damage response (DDR) (84.3% vs. 71.3%, P = 0.04) and p53 signaling (88.6% vs. 59.6%, P < 0.001) pathways. Additionally, 39.9% of patients with BTC harbored at least one actionable genomic alteration. Germline variants were detected in 7.0% (18/258) of patients, with the majority occurring in DDR (61.1%) and p53 (22.2%) pathways. Comparisons with the MSKCC cohort revealed similar genomic features and alterations. Patients with CCA exhibited significantly longer overall survival (OS) than patients with GBC (median OS, 41.2 vs. 24.3 months, P = 0.003). In the MSKCC cohort, high tumor mutational burden (TMB-H_med) correlated with poorer OS (HR = 1.43, P = 0.01), while PBRM1 mutations were associated with improved survival (HR = 0.50, P = 0.02). This study underscores the distinct genomic profiles of GBC and CCA, offering valuable insights into the molecular underpinnings of these aggressive cancers and supporting the development of precision medicine strategies.