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We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted\/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters\u2014fluke-positive CCAs (clusters 1\/2) are enriched in ERBB2 amplifications and TP53 mutations; conversely, fluke-negative CCAs (clusters 3\/4) exhibit high copy-number alterations and PD-1\/PD-L2 expression, or epigenetic mutations (IDH1\/2, BAP1) and FGFR\/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3\u2032 untranslated region deletion as a mechanism of FGFR2 upregulation. Integration of noncoding promoter mutations with protein\u2013DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores\u2014mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.<\/jats:p>\n                  <jats:p>Significance: Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes. Cancer Discov; 7(10); 1116\u201335. \u00a92017 AACR.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 1047<\/jats:p>","DOI":"10.1158\/2159-8290.cd-17-0368","type":"journal-article","created":{"date-parts":[[2017,6,30]],"date-time":"2017-06-30T20:25:41Z","timestamp":1498854341000},"page":"1116-1135","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":864,"title":["Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma"],"prefix":"10.1158","volume":"7","author":[{"given":"Apinya","family":"Jusakul","sequence":"first","affiliation":[{"name":"1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore."},{"name":"2Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore."},{"name":"3The Centre for Research and Development of Medical Diagnostic Laboratories and Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana","family":"Cutcutache","sequence":"additional","affiliation":[{"name":"4Centre for Computational Biology, Duke-NUS Medical School, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chern Han","family":"Yong","sequence":"additional","affiliation":[{"name":"1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore."},{"name":"4Centre for Computational Biology, Duke-NUS Medical School, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Quan","family":"Lim","sequence":"additional","affiliation":[{"name":"2Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore."},{"name":"5Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Division of Medical Oncology, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi Ni","family":"Huang","sequence":"additional","affiliation":[{"name":"4Centre for Computational Biology, Duke-NUS Medical School, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisha","family":"Padmanabhan","sequence":"additional","affiliation":[{"name":"1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishwa","family":"Nellore","sequence":"additional","affiliation":[{"name":"6Department of Biostatistics and Bioinformatics, Center for Genomic and Computational Biology, Duke University, Durham, North Carolina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarinya","family":"Kongpetch","sequence":"additional","affiliation":[{"name":"2Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, 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Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swe Swe","family":"Myint","sequence":"additional","affiliation":[{"name":"2Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raynoo","family":"Thanan","sequence":"additional","affiliation":[{"name":"12Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjanaa","family":"Nagarajan","sequence":"additional","affiliation":[{"name":"2Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weng Khong","family":"Lim","sequence":"additional","affiliation":[{"name":"1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore."},{"name":"2Laboratory of Cancer 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