{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T14:52:51Z","timestamp":1767797571133,"version":"3.49.0"},"reference-count":150,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Council of Thailand through the Fluke Free Thailand Project and the IMSUT Joint Research Project, the Institute of Medical Science, University of Tokyo, Japan for Watcharin Loilome"},{"name":"Walailak University under the New Researcher Development scheme","award":["WU69226"],"award-info":[{"award-number":["WU69226"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Cholangiocarcinoma (CCA) is a highly aggressive cancer of the biliary tract, distinguished by significant intratumoral heterogeneity (ITH), which contributes to therapy resistance and unfavorable clinical outcomes. Traditional genome profiling has revealed recurring driver changes in CCA; yet, genomic data alone fails to elucidate functional pathway activation, adaptive signaling, and the diverse treatment responses reported among tumor locations and disease subtypes. This review analyses the use of integrated sequencing technologies, proteogenomics, and phosphoproteomics to systematically characterize intratumoral heterogeneity in cholangiocarcinoma and convert molecular diversity into therapeutically applicable discoveries. We present evidence that the combination of genomic sequencing and mass spectrometry\u2013based proteomics facilitates the direct correlation of genetic mutations with protein expression, post-translational modifications, and signaling system activity. Phosphoproteomic profiling specifically offers functional insights into kinase-driven networks that dictate tumor aggressiveness, therapeutic susceptibility, and adaptive resistance mechanisms, which cannot be anticipated only from DNA-level analysis. We propose that integrating proteogenomic and phosphoproteomic analyses into diagnostic and therapeutic assessments can enhance molecular classification, reveal subtype- and region-specific therapeutic dependencies, and guide rational combination treatment strategies, based on recent extensive proteogenomic studies and functional proteomic investigations in CCA. Pathway-level analysis of intratumoral heterogeneity provides a framework for selecting targeted medicines, predicting resistance, and informing personalized treatment strategies in CCA. The combination of sequencing, proteogenomics, and phosphoproteomics is essential for advancing precision oncology in cholangiocarcinoma. The implementation of this multi-layered analytical approach may better patient classification, refine therapy choices, and eventually improve clinical outcomes for individuals with this particular heterogeneous cancer.<\/jats:p>","DOI":"10.3390\/medsci14010030","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T11:46:43Z","timestamp":1767786403000},"page":"30","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Sequencing and Proteogenomic Approaches to Intratumoral Heterogeneity in Cholangiocarcinoma: Implications for Precision Diagnosis and Therapy"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2939-1706","authenticated-orcid":false,"given":"Sirinya","family":"Sitthirak","sequence":"first","affiliation":[{"name":"Department of Medical Technology, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"Research Excellence Center for Innovation and Health Products (RECIHP), Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4536-4492","authenticated-orcid":false,"given":"Arporn","family":"Wangwiwatsin","sequence":"additional","affiliation":[{"name":"Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7652-7771","authenticated-orcid":false,"given":"Apinya","family":"Jusakul","sequence":"additional","affiliation":[{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6743-5047","authenticated-orcid":false,"given":"Nisana","family":"Namwat","sequence":"additional","affiliation":[{"name":"Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0209-3901","authenticated-orcid":false,"given":"Poramate","family":"Klanrit","sequence":"additional","affiliation":[{"name":"Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-8390","authenticated-orcid":false,"given":"Sittiruk","family":"Roytrakul","sequence":"additional","affiliation":[{"name":"National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4765-333X","authenticated-orcid":false,"given":"Hasaya","family":"Dokduang","sequence":"additional","affiliation":[{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Faculty of Medicine, Mahasarakham University, Mahasarakham 44000, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7404-6664","authenticated-orcid":false,"given":"Thitinat","family":"Duangchan","sequence":"additional","affiliation":[{"name":"Department of Medical Technology, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"Hematology and Transfusion Science Research Center, Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5413-6937","authenticated-orcid":false,"given":"Yanisa","family":"Rattanapan","sequence":"additional","affiliation":[{"name":"Department of Medical Technology, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"Hematology and Transfusion Science Research Center, Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Attapol","family":"Titapun","sequence":"additional","affiliation":[{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Apiwat","family":"Jareanrat","sequence":"additional","affiliation":[{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasin","family":"Thanasukarn","sequence":"additional","affiliation":[{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6689-2525","authenticated-orcid":false,"given":"Natcha","family":"Khuntikeo","sequence":"additional","affiliation":[{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teh Bin","family":"Tean","sequence":"additional","affiliation":[{"name":"National Cancer Centre Singapore, Duke-NUS Medical School, Singapore 169857, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke","family":"Boulter","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, Scotland, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshinori","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo 113-8602, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8572-5577","authenticated-orcid":false,"given":"Watcharin","family":"Loilome","sequence":"additional","affiliation":[{"name":"Department of Systems Biosciences and Computational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Li, Y., Ou, Z., Yu, D., He, H., Zheng, L., Chen, J., Chen, C., Xiong, H., and Chen, Q. 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