Molecular Subtypes of Cholangiocarcinoma and Their Translational Implications.

Cholangiocarcinomas show biologically distinct molecular subtypes that are not aligned with intrahepatic, perihilar, and distal surgical categories, including different genomic and genetic characteristics.

• Why it matters: Surgical delineation fails to reflect tumor biology, limiting translation of actionable targets and obscuring how etiologies, risk factors, and mutational processes shape treatment-relevant heterogeneity.
• What they did: The review synthesizes evidence on CCA etiologies, tumor molecular heterogeneity, mutational signatures linked to oxidative stress, aging, and exogenous exposures, and how replication timing, immunoselection, and metabolic pressures shape alteration patterns.
• The result: It highlights actionable target-rich subgroups—especially intrahepatic CCAs with relatively high percentages of fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase 1 or 2 mutations—supporting more biologically informed treatment strategies.

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