Oncogenesis in cholangiocarcinoma

Cholangiocarcinoma (CCA), a highly heterogeneous malignancy of the biliary tract, has emerged as a global health concern due to its rising incidence and poor prognosis. Its pathogenesis is shaped by complex interactions between environmental, infectious, and genetic factors, leading to dysregulation of key cellular pathways and molecular alterations. This review provides an in-depth analysis of the current understanding of CCA oncogenesis, focusing on the anatomical and histological subtypes, cellular sources, and the intricate genetic and epigenetic landscape that drives tumor initiation and progression. Key oncogenic alterations include mutations in KRAS, BRAF, IDH1/2, and PIK3CA, alongside inactivation of tumor suppressors such as TP53, CDKN2A, ARID1A, SMAD4, and BAP1. The dysregulation of core signaling pathways, RTK/PI3K/AKT/mTOR, MAPK/ERK, Wnt/β-catenin, TGF-β, Notch, and Hedgehog, is explored in detail, highlighting their roles in cell proliferation, survival, and tumor progression. Furthermore, the review examines the contribution of chronic inflammation, liver fluke infections, viral hepatitis, and environmental carcinogens in promoting genomic instability and malignant transformation. A global understanding of these molecular mechanisms is essential for advancing precision medicine in CCA and guiding the development of targeted therapies.