Epigenome‐Wide Analysis of Methylation Changes in the Sequence of Gallstone Disease, Dysplasia, and Gallbladder Cancer

作者：Johannes Brägelmann, Carol Barahona Ponce, Katherine Marcelain, Stéphanie Roessler, Benjamin Goeppert, Iván Gallegos, Alicia Colombo, Verónica Sanhueza, Erik Morales, María Teresa Rivera, Gonzalo de Toro, Alejandro Ortega, Bettina Müller, Fernando Gabler, Dominique Scherer, Mélanie Waldenberger, Eva Reischl, Felix Boekstegers, Valentina Gárate‐Calderón, Sinan U. Umu, Trine B. Rounge, Odilia Popanda, Justo Lorenzo Bermejo · 发表于：Hepatology · 年份：2020 · DOI：10.1002/hep.31585 · 被引用次数：55 · 研究领域：Cholangiocarcinoma and Gallbladder Cancer Studies、Gallbladder and Bile Duct Disorders、Pancreatic and Hepatic Oncology Research

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...