{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T13:41:40Z","timestamp":1770471700792,"version":"3.49.0"},"reference-count":168,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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\u2015such as FGFR2 fusions, IDH1 mutations, and ERBB2 amplification\u2015that 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\u2015including FGFR2 fusions, IDH1 mutations, and ERBB2 amplification\u2015are 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.<\/jats:p>","DOI":"10.3390\/cancers17183052","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T12:24:25Z","timestamp":1758198265000},"page":"3052","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Chronic Liver Disease Associated Cholangiocarcinoma: Genomic Insights and Precision Therapeutic Strategies"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9531-7240","authenticated-orcid":false,"given":"Kyoko","family":"Oura","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0760-3045","authenticated-orcid":false,"given":"Asahiro","family":"Morishita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3227-0801","authenticated-orcid":false,"given":"Mai","family":"Nakahara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9975-386X","authenticated-orcid":false,"given":"Tomoko","family":"Tadokoro","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joji","family":"Tani","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsutomu","family":"Masaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kagawa Saiseikai Hospital, Takamatsu 761-8076, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideki","family":"Kobara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: The next horizon in mechanisms and management","volume":"17","author":"Banales","year":"2020","journal-title":"Nat. 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