Molecular Subtypes of Cholangiocarcinoma and Their Translational Implications

Cholangiocarcinomas (CCAs) are cancers that arise in the peripheral or central bile ducts. They have substantial heterogeneity in their etiologies and histopathologic phenotypes, ranging from cholangiolar carcinomas arising from the smallest bile ducts or from dedifferentiating hepatocytes through cellular plasticity, to ductular cancers in medium and large-sized bile ducts. The surgical delineation of intrahepatic, perihilar, and distal CCAs does not match the biological classification, as intrahepatic CCAs include both small duct cholangiolar carcinoma and intermediate duct ductular or mucinous CCAs, which have different genomic and genetic characteristics. Despite their overall poor prognosis, CCAs have proven to include the most actionable target-rich types of cancer, with intrahepatic CCAs including relatively high percentages of fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase 1 or 2 mutations, as well as other currently or potentially targetable aberrations. We discuss the etiologies and risk factors for CCAs, review the pathophysiologic basis for tumor molecular heterogeneity in CCA, and discuss the known links with mutational signatures in subgroups of CCA, such as oxidative stress, aging, and exogenous exposures. The potential roles of differences in cell type-specific replication timing and immunoselective and metabolic pressures are discussed, as are the implications of synergistic or antagonistic oncogenic effects, leading to unique patterns of co-occurrence vs mutual exclusivity of alterations. In addition, we review the impacts of common genetic variants and known pathogenic germline or somatic variants that predispose carriers to CCA. Finally, we discuss the role of epigenetics and variations in DNA methylation in heterogeneity of CCA within the context of evolving treatment options and remaining key gaps in knowledge.