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

Abstract

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. 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. 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). <i>TP53</i> (54%) and <i>ERBB2</i> (15%; approximately equal to 8% amplification, with S310F/Y hotspot predominance) were the most common alterations, followed by <i>CDKN2A</i> (9%), <i>KRAS</i> (7%), and <i>SMAD4</i> (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 <i>ARID1A</i>, <i>SMAD4</i>, and <i>CDKN2A</i> alterations (all <i>P</i> < .001). In 37 cfDNA patients, 13 showed no variants, but detected alterations that qualitatively mirrored tissue findings. This comprehensive genomic study of Indian GBC defines a distinct mutation map with region-specific drivers, notably <i>ERBB2</i>, 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.