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Brägelmann, J.* ; Barahona Ponce, C.* ; Marcelain, K.* ; Roessler, S.* ; Goeppert, B.* ; Gallegos, I.* ; Colombo, A.* ; Sanhueza, V.* ; Morales, E.* ; Rivera, M.T.* ; de Toro, G.* ; Ortega, A.* ; Müller, B.* ; Gabler, F.* ; Scherer, D.* ; Waldenberger, M. ; Reischl, E. ; Boekstegers, F.* ; Garate-Calderon, V.* ; Umu, S.U.* ; Rounge, T.B.* ; Popanda, O.* ; Lorenzo Bermejo, J.*

Epigenome-wide analysis of methylation changes in the sequence of gallstone disease, dysplasia, and gallbladder cancer.

Hepatology 73, 2293-2310 (2021)
Publ. Version/Full Text DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
BACKGROUND & AIMS: Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low- 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: To perform epigenome-wide methylation profiling, genomic DNA extracted from sections of FFPE gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Pre-processed, 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). MAIN RESULTS: The number and magnitude of epigenetic changes increased with disease development and predominantly involved the hypermethylation of CpG 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 CDKN2A, MDM2, TP53, and CCND1. Gains in the targetable ERBB2 were detected in 14% of the 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Chile ; Dna Methylation ; Epigenetics ; Gallbladder Cancer; Promotes Tumor-metastasis; Epigenetic Signature; Therapeutic Target; Signaling Pathway; Hypermethylation; Epidemiology; Carcinoma; Biomarker; Profile; Genes
ISSN (print) / ISBN 0270-9139
e-ISSN 1527-3350
Journal Hepatology
Quellenangaben Volume: 73, Issue: 6, Pages: 2293-2310 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Hoboken, NJ
Reviewing status Peer reviewed
Grants Projekt DEAL