Background: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy arising from the biliary epithelium, with an increasing incidence and poor prognosis worldwide. Recent advances in next-generation sequencing have revealed a variety of genomic alterations―such as FGFR2 fusions, IDH1 mutations, and ERBB2 amplification―that may serve as therapeutic targets. However, the influence of underlying etiologic factors, including chronic liver and biliary diseases, on the molecular landscape of CCA remains unclear.Objective: This review aimed to synthesize the current knowledge on the genomic and molecular alterations of CCA in the context of diverse etiologic factors, including hepatitis B virus, hepatitis C virus, primary sclerosing cholangitis (PSC), primary biliary cholangitis, metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and liver fluke infection.Main findings: Certain backgrounds, such as PSC and liver fluke infection, are associated with distinct molecular signatures (e.g., TP53, SMAD4, KRAS, and ERBB2 alterations), whereas others, such as MASLD or ALD, show limited and inconsistent genomic data. Targetable alterations―including FGFR2 fusions, IDH1 mutations, and ERBB2 amplification―are heterogeneously distributed across etiologies and anatomical subtypes. Molecular targeted therapies such as FGFR and IDH1 inhibitors have shown clinical benefits in selected patients.Conclusions: A better understanding of how chronic liver and biliary diseases shape the genomic landscape of CCA will inform the development of personalized treatments, surveillance strategies, and preventive approaches. Large-scale etiology-stratified genomic studies integrating multiomics and real-world clinical data are urgently needed to advance precision oncology in CCA.
背景：胆管癌是一种源于胆管上皮的高度异质性恶性肿瘤，全球范围内发病率持续上升且预后不良。新一代测序技术的进展揭示了多种基因组改变（如FGFR2融合、IDH1突变和ERBB2扩增）可能成为治疗靶点。然而，慢性肝胆疾病等潜在病因因素对胆管癌分子特征的影响尚不明确。 目的：本综述旨在整合当前关于不同病因背景下胆管癌基因组与分子改变的研究进展，涵盖乙型肝炎病毒、丙型肝炎病毒、原发性硬化性胆管炎、原发性胆汁性胆管炎、代谢功能障碍相关脂肪性肝病、酒精相关性肝病以及肝吸虫感染等病因因素。 主要发现：特定病因背景（如原发性硬化性胆管炎和肝吸虫感染）与特征性分子标志相关（如TP53、SMAD4、KRAS和ERBB2改变），而代谢功能障碍相关脂肪性肝病或酒精相关性肝病等病因的基因组数据则有限且不一致。可靶向的基因改变（包括FGFR2融合、IDH1突变和ERBB2扩增）在不同病因和解剖亚型中呈现异质性分布。FGFR抑制剂和IDH1抑制剂等分子靶向治疗已在特定患者群体中显示出临床获益。 结论：深入理解慢性肝胆疾病如何塑造胆管癌的基因组特征，将有助于推动个体化治疗、监测策略及预防措施的制定。当前亟需开展整合多组学与真实世界临床数据的大规模病因分层基因组研究，以促进胆管癌精准肿瘤学的发展。
肿瘤(癌症)患者之家