Genomic Landscape of Cholangiocarcinoma in India: Ethnic Variants and Implications for Targeted Therapy

Background Cholangiocarcinoma (CCA) is a molecularly heterogeneous malignancy of the biliary tract, with rising incidence globally and distinct geographic variations in oncogenic drivers. Despite India’s significant cancer burden, data on the molecular landscape of CCA in Indian patients remain sparse, limiting the development of targeted therapies. Methods This retrospective study analyzed molecular data from 220 Indian patients with CCA, including 63 intrahepatic (ICA) and 10 extrahepatic (ECA) cases, while the remaining 147 cases were reported as CCA without further subtyping. The molecular data were analysed across three institutions using multiple validated next-generation sequencing (NGS) platforms. Genomic profiles were compared to international datasets from cBioPortal to identify ethnically distinct mutation patterns. Findings: Among 147 CCA cases with complete data, TP53 (35 ·6%), IDH1 (9·5%), KRAS (7·9%), and PIK3CA (7·9%) were the most frequently mutated genes. TP53 and KRAS mutation rates were significantly higher in the Indian cohort compared to cBioPortal, while alterations in ARID1A , BAP1 , FGFR2 , and SMAD4 were notably lower. Tumor mutation burden was predominantly low, and microsatellite instability was rare. Distinct non-fusion FGFR2 alterations and a broader spectrum of PI3K pathway mutations were also observed. Compared to international data, Indian ICC cases showed reduced frequencies of IDH1 and FGFR2 mutations and a higher male-to-female ratio. Interpretation: This is one of the first large-scale genomic studies of CCA in Indian patients, revealing significant differences in mutational profiles compared to global datasets. These findings emphasize the importance of region-specific molecular profiling to inform precision oncology strategies in biliary tract cancers.