Abstract
BACKGROUND: Biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CCA), are rare but aggressive malignancies with distinct molecular landscapes and poor prognoses. Genomic profiling has revealed significant molecular alterations, but the genomic landscape of BTC in the Indian population remains underexplored. This study aims to comprehensively characterize the mutation landscape of BTC in the Indian population. METHODS: A total of 154 BTC cases, including 69 CCA and 85 GBC, were retrospectively analyzed using data collected from various targeted sequencing panels. Somatic mutations, copy number variations (CNVs), and gene fusions in key oncogenic and tumor suppressor genes were identified from these panel reports. Downstream analyses were performed to derive key biological insights, including pathway enrichment and mutual exclusivity and co-occurrence analyses of genomic alterations. RESULTS: TP53 was the most frequently mutated gene (53%), followed by KRAS (18%), ARID1A (9%), IDH1 (7%), and PIK3CA (7%). Recurrent amplifications were observed in MYC (12%) and ERBB2 (9%). Pathway enrichment analysis revealed significant dysregulation in the PI3K-AKT-mTOR, Notch, and Wnt/β-catenin signaling pathways. Notably, IDH1 mutations were primarily observed in CCA, while STK11 mutations were exclusive to GBC, highlighting distinct molecular characteristics between the two subtypes. PD-L1-negative tumors exhibited distinct genomic alterations, notably SMAD4 mutations, which were associated with reduced PD-L1 expression. This loss of SMAD4, involved in TGF-β signaling, could impair immune response regulation and facilitate immune evasion. CONCLUSIONS: This study provides a comprehensive molecular profiling of BTCs in the Indian population, revealing key genomic alterations, subtype-specific differences, and associations with immune features. The findings underscore the importance of molecular profiling in guiding personalized treatment strategies.