Abstract
Introduction
Cholangiocarcinoma (CCA) and gallbladder adenocarcinoma (GBC) are rare, aggressive epithelial malignancies that are clinically classified together as biliary tract cancers (BTCs). Recent single-institution studies suggest they possess distinct molecular characteristics and therapeutic vulnerabilities. However, comprehensive genomic comparisons between these malignancies remain limited. This study compares the genomic landscapes of CCA and GBC for disease classification and identification of actionable treatment targets.
Methods
Genomic and clinical data were obtained from The Cancer Genome Atlas through cBioPortal. CCA (n = 984 patients) and GBC (n = 932 patients) cases were selected using cancer type and primary tumor site classifications excluding metastatic disease and mixed histologies. Clinicopathologic characteristics, including nonsynonymous tumor mutational burden (TMB), TMB score, fraction genome altered (FGA), somatic mutations, copy number alterations (CNAs), co-mutation frequencies, gene enrichments, and survivorship were compared between cohorts. Statistical comparisons were performed using Kaplan-Meier (KM), Wilcoxon, two-sided Fisher exact, and Cox proportional hazards tests, with P 0.05 considered significant. Potentially actionable targets were referenced using OncoKB. For survivorship analyses, cohorts were further stratified to include only patients with overall survival calculated from the date of diagnosis to death or last follow-up (CCA, n = 176; GBC, n = 112). The most frequently altered genes within each cohort were binarized (mutant = 1, wild-type = 0) for KM and Cox hazards analyses.
Results
Patients with CCA demonstrated significantly longer median overall survival than GBC (P 0.01). GBC exhibited significantly higher median nonsynonymous TMB and TMB scores than CCA (P 0.01), whereas FGA and CNAs did not differ significantly. CCA demonstrated genomic enrichments involving receptor tyrosine kinase signaling, DNA repair, and cellular metabolism, whereas GBC demonstrated enrichments in tumor suppressor loss, TGF-β signaling, PI3K pathway alterations, and cell-cycle dysregulation. CCA was enriched for concurrent co-mutations involving chromatin remodeling, DNA repair, and receptor tyrosine kinase signaling, whereas GBC demonstrated co-occurring alterations involving tumor suppressor loss, chromatin remodeling, TGF-β signaling, and PI3K pathways. Survivorship analyses identified ARID1A mutations, PBRM1 mutations, and concurrent ARID1A-TP53 alterations as significantly associated with poorer overall survival in CCA, whereas no significant survival-associated genomic alterations were identified in GBC.
Conclusion
CCA and GBC demonstrate distinct clinical and genomic characteristics despite their current classification as BTCs. These findings support recognition of CCA and GBC as biologically distinct malignancies that may benefit from disease-specific therapeutic strategies.