The molecular landscape and clinical nomogram of cholangiocarcinoma harboring ESCAT I alterations.

4158 Background: Cholangiocarcinoma (CCA) is the second most common primary liver cancer, with rising global incidence and mortality. Despite molecular advances, most patients present with advanced disease unsuitable for curative resection, resulting in poor prognosis. ESCAT I alterations, including FGFR2 fusions, IDH1/IDH2 mutations, BRAF V600E, HER2 amplification, MSI-high, and NTRK fusions, represent validated therapeutic targets with FDA/EMA-approved treatments, occurring in 25% of CCAs. Here, we analyze genomic and transcriptomic data to characterize the molecular landscape and develop an OS nomogram for CCA patients with ESCAT I alterations. Methods: In this retrospective study, we analyzed publicly available data from 1928 CCA patients, enrolled in participating institutions between 2012 and 2022, sourced from the cBioPortal for Cancer Genomics. We investigated frequencies of ESCAT I alterations, copy number alterations, mRNA expression, clinicopathological factors, and OS. Transcriptomic profiling and pathway enrichment analysis identified survival-associated genes. A nomogram integrating clinical, pathological, and molecular features was constructed and validated for OS prediction. Results: Genomic analysis of 1,845 CCA samples revealed revealed IDH1 mutations (12%), FGFR2 fusions (8%), HER2 amplification (6%), BRAF V600E (4%), MSI-high (4%), NTRK1/2/3 fusions (3.4%) and IDH2 mutations (2%). Notably, ESCAT I alterations were associated with inferior OS (log-rank P = 0.009; mOS altered vs wild-type 33.84 vs 24.31 months). Transcriptomic and GSEA profiling linked these alterations to dysregulation of oncogenic pathways, including DNA damage repair, cell cycle regulation, epithelial-mesenchymal transition, and immune pathways. The prognostic nomogram incorporated age, stage, differentiation, ESCAT I subtype, and top 5 most significantly identified transcriptomic signatures. Conclusions: This study provides comprehensive molecular characterization of ESCAT I-altered CCA, revealing distinct genomic and transcriptomic profiles associated with specific alterations and oncogenic pathway dysregulation. The validated nomogram offers a practical tool for personalized OS prediction, potentially guiding treatment selection, surveillance intensity, and clinical trial stratification. These findings emphasize the importance of routine molecular profiling in CCA and support precision medicine integration to improve outcomes and target therapy resistance mechanisms in this population.