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. 2021 Jun;73(6):2293-2310.
doi: 10.1002/hep.31585. Epub 2021 Jun 15.

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

Johannes Brägelmann  1   2   3 , Carol Barahona Ponce  1   4 , Katherine Marcelain  4 , Stephanie Roessler  5 , Benjamin Goeppert  5 , Ivan Gallegos  6 , Alicia Colombo  4   6 , Verónica Sanhueza  7 , Erik Morales  8 , María Teresa Rivera  9 , Gonzalo de Toro  10 , Alejandro Ortega  11 , Bettina Müller  12 , Fernando Gabler  13 , Dominique Scherer  1 , Melanie Waldenberger  14 , Eva Reischl  14 , Felix Boekstegers  1 , Valentina Garate-Calderon  1   4 , Sinan U Umu  15 , Trine B Rounge  15   16 , Odilia Popanda  17 , Justo Lorenzo Bermejo  1
Affiliations

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

Johannes Brägelmann et al. Hepatology. 2021 Jun.

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.

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