Braegelmann, Johannes, Barahona Ponce, Carol, Marcelain, Katherine, Roessler, Stephanie ORCID: 0000-0002-5333-5942, Goeppert, Benjamin, Gallegos, Ivan, Colombo, Alicia, Sanhueza, Veronica, Morales, Erik, Rivera, Maria Teresa, de Toro, Gonzalo, Ortega, Alejandro, Muller, Bettina, Gabler, Fernando, Scherer, Dominique, Waldenberger, Melanie, Reischl, Eva, Boekstegers, Felix, Garate-Calderon, Valentina, Umu, Sinan U., Rounge, Trine B., Popanda, Odilia and Lorenzo Bermejo, Justo (2021). Epigenome-Wide Analysis of Methylation Changes in the Sequence of Gallstone Disease, Dysplasia, and Gallbladder Cancer. Hepatology, 73 (6). S. 2293 - 2311. HOBOKEN: WILEY. ISSN 1527-3350

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Abstract

Background and Aims Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low-income and middle-income 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 -> dysplasia -> GBC in Chile, the country with the highest incidence of GBC worldwide. Approach and Results To perform epigenome-wide methylation profiling, genomic DNA extracted from sections of formalin-fixed, paraffin-embedded gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Preprocessed, quality-controlled data from 82 samples (gallstones n = 32, low-grade dysplasia n = 13, high-grade dysplasia n = 9, GBC n = 28) 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-guanine 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-dependent kinase inhibitor 2A, MDM2 proto-oncogene, tumor protein P53, and cyclin D1 genes. Gains in the targetable Erb-B2 receptor tyrosine kinase 2 gene were detected in 14% of GBC samples. Conclusions Our results indicate that GBC carcinogenesis comprises three main methylation stages: early (gallstone disease and low-grade dysplasia), intermediate (high-grade 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Braegelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barahona Ponce, CarolUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marcelain, KatherineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roessler, StephanieUNSPECIFIEDorcid.org/0000-0002-5333-5942UNSPECIFIED
Goeppert, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gallegos, IvanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Colombo, AliciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanhueza, VeronicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morales, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rivera, Maria TeresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Toro, GonzaloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortega, AlejandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muller, BettinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabler, FernandoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scherer, DominiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waldenberger, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reischl, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boekstegers, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garate-Calderon, ValentinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Umu, Sinan U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rounge, Trine B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Popanda, OdiliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenzo Bermejo, JustoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-602273
DOI: 10.1002/hep.31585
Journal or Publication Title: Hepatology
Volume: 73
Number: 6
Page Range: S. 2293 - 2311
Date: 2021
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1527-3350
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROMOTES TUMOR-METASTASIS; EPIGENETIC SIGNATURE; THERAPEUTIC TARGET; SIGNALING PATHWAY; HYPERMETHYLATION; EPIDEMIOLOGY; CARCINOMA; BIOMARKER; PROFILE; GENESMultiple languages
Gastroenterology & HepatologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60227

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