Genomic Profiling of Indian Gallbladder Carcinoma: Mutational Insights in a High-Incidence Population

PURPOSE – Gallbladder carcinoma (GBC) has a disproportionately high incidence rate in India; however, genomic data remain sparse and inconsistent. We conducted a comprehensive genomic analysis of Indian GBC and compared its mutational profile with that of international cohorts to identify region-specific oncogenic drivers.MATERIALS AND METHODS – This retrospective study analyzed 376 patients with GBC (339 tissue and 37 plasma cell free DNA [cfDNA] samples) from three Indian institutions (2022-2024) using clinically validated next-generation sequencing (NGS) panels. Genomic data were compared with curated cohorts from cBioPortal, including Western (White), Asian, and multiethnic data sets. Mutation frequencies were assessed, and statistical comparisons were performed.RESULTS – GBC was more frequent in women (female:male 1.5:1) and was diagnosed nearly a decade earlier than in international cohorts (median age, 54 years). TP53 (54%) and ERBB2 (15%; approximately equal to 8% amplification, with S310F/Y hotspot predominance) were the most common alterations, followed by CDKN2A (9%), KRAS (7%), and SMAD4 (7%). Microsatellite instability-high (0.6%, 2 of 170 tested) and tumor mutational burden-high (1.3%, 1 of 79 tested) tumors were rare. Compared with Western and Asian cohorts, Indian patients with GBC had significantly lower ARID1A, SMAD4, and CDKN2A alterations (all P < .001). In 37 cfDNA patients, 13 showed no variants, but detected alterations that qualitatively mirrored tissue findings.CONCLUSION – This comprehensive genomic study of Indian GBC defines a distinct mutation map with region-specific drivers, notably ERBB2, supporting precision oncology and the real-world feasibility of liquid biopsy. The use of heterogeneous NGS panels across institutions remains a key limitation, introducing variability in frequency estimates, but the findings provide a foundation for region-tailored therapeutic strategies and prospective genomic correlations.