{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T16:08:15Z","timestamp":1791648495539,"version":"4.3.4"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low\u2010income and middle\u2010income countries, and research into this disease has long been limited. In this study we therefore investigate the epigenetic changes along the model of GBC carcinogenesis represented by the sequence gallstone disease \u2192 dysplasia \u2192 GBC in Chile, the country with the highest incidence of GBC worldwide.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>To perform epigenome\u2010wide methylation profiling, genomic DNA extracted from sections of formalin\u2010fixed, paraffin\u2010embedded gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Preprocessed, quality\u2010controlled data from 82 samples (gallstones n\u00a0=\u00a032, low\u2010grade dysplasia n\u00a0=\u00a013, high\u2010grade dysplasia n\u00a0=\u00a09, GBC n\u00a0=\u00a028) were available to identify differentially methylated markers, regions, and pathways as well as changes in copy number variations (CNVs). The number and magnitude of epigenetic changes increased with disease development and predominantly involved the hypermethylation of cytosine\u2013guanine dinucleotide islands and gene promoter regions. The methylation of genes implicated in Wnt signaling, Hedgehog signaling, and tumor suppression increased with tumor grade. CNVs also increased with GBC development and affected cyclin\u2010dependent kinase inhibitor 2A, MDM2 proto\u2010oncogene, tumor protein P53, and cyclin D1 genes. Gains in the targetable Erb\u2010B2 receptor tyrosine kinase 2 gene were detected in 14% of GBC samples.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our results indicate that GBC carcinogenesis comprises three main methylation stages: early (gallstone disease and low\u2010grade dysplasia), intermediate (high\u2010grade dysplasia), and late (GBC). The identified gradual changes in methylation and CNVs may help to enhance our understanding of the mechanisms underlying this aggressive disease and eventually lead to improved treatment and early diagnosis of GBC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31585","type":"journal-article","created":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T23:31:18Z","timestamp":1601940678000},"page":"2293-2310","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":47,"title":["Epigenome\u2010Wide Analysis of Methylation Changes in the Sequence of Gallstone Disease, Dysplasia, and Gallbladder Cancer"],"prefix":"10.1097","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1306-2169","authenticated-orcid":false,"given":"Johannes","family":"Br\u00e4gelmann","sequence":"first","affiliation":[{"name":"Statistical Genetics Research Group,Institute of Medical Biometry and Informatic,University of Heidelberg,Heidelberg,Germany"},{"name":"Molecular Pathology,Institute of Pathology & Department of Translational Genomics,University Hospital of Cologne,Cologne,Germany"},{"name":"Mildred Scheel School of Oncology,Medical Faculty,University Hospital Cologne,Cologne,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Barahona Ponce","sequence":"additional","affiliation":[{"name":"Statistical Genetics Research Group,Institute of Medical Biometry and Informatic,University of Heidelberg,Heidelberg,Germany"},{"name":"Department of Basic and Clinical Oncology,Medical Faculty,University of Chile,Santiago,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Marcelain","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Oncology,Medical Faculty,University of Chile,Santiago,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Roessler","sequence":"additional","affiliation":[{"name":"Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Goeppert","sequence":"additional","affiliation":[{"name":"Institute of Pathology,University Hospital Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Gallegos","sequence":"additional","affiliation":[{"name":"Servicio de Anatom\u00eda Patol\u00f3gica,Hospital Cl\u00ednico de la Universidad de Chile,Santiago,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Colombo","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Oncology,Medical Faculty,University of Chile,Santiago,Chile"},{"name":"Servicio de Anatom\u00eda Patol\u00f3gica,Hospital Cl\u00ednico de la Universidad de Chile,Santiago,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f3nica","family":"Sanhueza","sequence":"additional","affiliation":[{"name":"Servicio de Anatom\u00eda Patol\u00f3gica,Hospital Padre Hurtado,Santiago,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Morales","sequence":"additional","affiliation":[{"name":"Facultad de Medicina,Universidad Catolica del Maule & Unidad de Anatomia Patologica del Hospital Regional de Talca,Talca,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Teresa","family":"Rivera","sequence":"additional","affiliation":[{"name":"Servicio de Anatom\u00eda Patol\u00f3gica,Hospital del Salvador,Santiago,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"de Toro","sequence":"additional","affiliation":[{"name":"Escuela de Tecnologia Medica,Universidad Austral de Chile sede Puerto Montt & Servicio de Anatom\u00eda Patol\u00f3gica,Hospital de Puerto Montt,Puerto Montt,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Ortega","sequence":"additional","affiliation":[{"name":"Servicio de Anatom\u00eda Patol\u00f3gica,Hospital Regional,Arica,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Servicio de Oncolog\u00eda M\u00e9dica,Instituto Nacional del C\u00e1ncer,Santiago,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Gabler","sequence":"additional","affiliation":[{"name":"Unidad de Anatomia Patologica,Hospital San Borja Arriaran,Santiago,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Scherer","sequence":"additional","affiliation":[{"name":"Statistical Genetics Research Group,Institute of Medical Biometry and Informatic,University of Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Waldenberger","sequence":"additional","affiliation":[{"name":"Research Unit of Molecular Epidemiology and Institute of Epidemiology,Helmholtz Zentrum M\u00fcnchen,German Research Center for Environmental Health,Neuherberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Reischl","sequence":"additional","affiliation":[{"name":"Research Unit of Molecular Epidemiology and Institute of Epidemiology,Helmholtz Zentrum M\u00fcnchen,German Research Center for Environmental Health,Neuherberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0587-7624","authenticated-orcid":false,"given":"Felix","family":"Boekstegers","sequence":"additional","affiliation":[{"name":"Statistical Genetics Research Group,Institute of Medical Biometry and Informatic,University of Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Garate\u2010Calderon","sequence":"additional","affiliation":[{"name":"Statistical Genetics Research Group,Institute of Medical Biometry and Informatic,University of Heidelberg,Heidelberg,Germany"},{"name":"Department of Basic and Clinical Oncology,Medical Faculty,University of Chile,Santiago,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinan U.","family":"Umu","sequence":"additional","affiliation":[{"name":"Department of Research,Cancer Registry of Norway,Oslo,Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trine B.","family":"Rounge","sequence":"additional","affiliation":[{"name":"Department of Research,Cancer Registry of Norway,Oslo,Norway"},{"name":"Department of Informatics,University of 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