{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T11:59:45Z","timestamp":1776686385925,"version":"3.51.2"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2021,11,27]],"date-time":"2021-11-27T00:00:00Z","timestamp":1637971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,11,27]],"date-time":"2021-11-27T00:00:00Z","timestamp":1637971200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Intrahepatic cholangiocarcinoma (ICC) is aggressive and has high rates of relapse, conferring poor long\u2010term survival after curative resection. Little is known about the genomic evolution that occurs during ICC relapse.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We conducted whole\u2010exome sequencing of 30 paired primary and relapsed tumors from 10 patients with ICC who received curative resection. We sought to identify frequently altered genes, infer tumor subclonal architectures, and track genomic evolution from primary to relapsed tumors. We examined functional effects and the mechanism of action of <jats:italic toggle=\"yes\">SLIT2<\/jats:italic>, a gene specifically mutated in relapsed tumors, on tumor growth and metastasis and the tumor microenvironment. Our results indicated that relapsed ICCs were genetically derived from intrahepatic dissemination of primary tumors. However, they acquired additional mutations while maintaining most drivers, such as <jats:italic toggle=\"yes\">TP53<\/jats:italic> and <jats:italic toggle=\"yes\">IDH1<\/jats:italic>. Multiregion sequencing suggested polyclonal seeding of ICC dissemination. Four of 10 relapsed ICCs acquired <jats:italic toggle=\"yes\">SLIT2<\/jats:italic> mutations that were not present in the corresponding primary tumors. Validation in an expanded sample revealed <jats:italic toggle=\"yes\">SLIT2<\/jats:italic> mutations in 2.3% (1\/44) of primary ICCs and 29.5% (13\/44) of relapsed ICCs. Biofunctional investigations revealed that inactivating mutation of <jats:italic toggle=\"yes\">SLIT2<\/jats:italic> resulted in activation of PI3K\u2013Akt signaling in ICC cells, directly enhanced neutrophil chemotaxis, mediated tumor\u2010associated neutrophil infiltration, and contributed to ICC growth and metastasis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>We characterized genomic evolution during ICC relapse and identified <jats:italic toggle=\"yes\">SLIT2<\/jats:italic> as a driver of tumor dissemination and tumor\u2010associated neutrophil infiltration.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32164","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T14:30:14Z","timestamp":1632148214000},"page":"831-846","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":15,"title":["Genomic evolution and the impact of SLIT2 mutation in relapsed intrahepatic cholangiocarcinoma"],"prefix":"10.1097","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8526-5221","authenticated-orcid":false,"given":"Shao\u2010Lai","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Liver Surgery and Transplantation,Liver Cancer Institute,Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chu\u2010Bin","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery and Transplantation,Liver Cancer Institute,Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng\u2010Li","family":"Song","sequence":"additional","affiliation":[{"name":"Institute of Cancer Stem Cell,Dalian Medical University,Dalian,Liaoning,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng\u2010Jun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery and Transplantation,Liver Cancer Institute,Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao\u2010Yang","family":"Xin","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery and Transplantation,Liver Cancer Institute,Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi\u2010Qiang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery and Transplantation,Liver Cancer Institute,Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong\u2010Qi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery and Transplantation,Liver Cancer Institute,Zhongshan Hospital,Fudan University,Shanghai,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery and Transplantation,Liver Cancer Institute,Zhongshan Hospital,Fudan University,Shanghai,China"},{"name":"State Key Laboratory of Genetic Engineering,Fudan University,Shanghai,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2118-1117","authenticated-orcid":false,"given":"Jian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery and Transplantation,Liver Cancer Institute,Zhongshan Hospital,Fudan University,Shanghai,China"},{"name":"State Key Laboratory of Genetic Engineering,Fudan University,Shanghai,China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2021,11,27]]},"reference":[{"issue":"1","key":"hep32164-bib-0001-20250824","first-page":"7","article-title":"Cancer statistics, 2019","volume":"69","year":"2019","journal-title":"CA Cancer J Clin"},{"key":"hep32164-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/j.jhep.2014.01.021","article-title":"Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma","volume":"60","year":"2014","journal-title":"J Hepatol"},{"issue":"6","key":"hep32164-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1053\/j.gastro.2013.10.013","article-title":"Pathogenesis, diagnosis, and management of cholangiocarcinoma","volume":"145","year":"2013","journal-title":"Gastroenterology"},{"issue":"6","key":"hep32164-bib-0004-20250824","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1001\/jamasurg.2013.5137","article-title":"Treatment and prognosis for patients with intrahepatic cholangiocarcinoma. 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