Impact of population-specific <i>KRAS</i> alterations on therapeutic vulnerabilities in cholangiocarcinoma: Evidence from a global meta-analysis.

Abstract

e16494 Background: Cholangiocarcinoma (CCA) exhibits marked molecular heterogeneity with significant geographic variation, limiting the generalizability of therapeutic strategies. While multiple genomic studies have characterized CCA, a comprehensive cross-country synthesis of patient-level mutational and clinically actionable alterations remains limited. We performed a meta-analysis integrating global sequencing datasets to define the genomic landscape, pathway dysregulation, and therapeutic relevance of somatic mutations in CCA. Methods: A systematic literature search of PubMed and Google Scholar identified sequencing-based CCA studies published within the last five years. Studies with patient-level clinical and mutational data were included, while those lacking detailed annotations were excluded. Somatic mutation data from 11 eligible studies across 9 countries were curated and integrated with publicly available MSK and TCGA CCA cohorts. Co-occurrence and mutual exclusivity were evaluated using Fisher’s exact test with Benjamini-Hochberg correction (q &lt; 0.05). Pathway enrichment analysis was conducted using Enrichr with the Panther 2016 gene set. Therapeutic actionability was assessed using OncoKB classification. Results: A total of 1,613 CCA samples were analyzed. TP53 (39%) and KRAS (22%) were the most frequently mutated genes across all cohorts. Significant country-specific differences were observed, with TP53 (40%) and KRAS (22%) mutation frequencies in the Indian cohort being significantly higher than those in the MSK ( TP53 : 18.16%; KRAS : 10.45%) and TCGA cohorts ( TP53 : 9.68%; KRAS : 10.45%). Additionally, population-specific KRAS variants (p.G12R, p.G12V, p.G12D) observed exclusively in Indian patients and classified as Level 2 actionable alterations. Compared with the Indian cohort ( IDH1 : 14%; SMAD4 : 8%), the MSK dataset showed a higher IDH1 mutation frequency (22.89% vs 7%, p &lt; 0.01) and a lower SMAD4 mutation frequency (2.49% vs 12%, p &lt; 0.01). Distinct co-occurrence and mutual exclusivity patterns were observed between intrahepatic and extrahepatic CCA, with KRAS showing mutual exclusivity with IDH1 , BRAF , and BAP1 , particularly in iCCA. Conclusions: This comprehensive meta-analysis highlights significant geographic heterogeneity in CCA genomics, with KRAS emerging as a dominant and clinically relevant driver in the Indian population. The distinct KRAS mutation spectrum observed in Indian patients underscores the need for region-specific precision oncology strategies and supports the evaluation of KRAS -directed therapies in this population.