Epigenome-wide analysis of methylation changes in the sequence of gallstone disease, dysplasia, and gallbladder cancer
Author
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Brägelmann, Johannes
Author
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Barahona Ponce, Carol Mariom
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Marcelain Cubillos, Katherine Jenny
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Roessler, Stephanie
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Goeppert, Benjamín
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Gallegos, Iván
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Colombo, Alicia
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Sanhueza, Verónica
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Morales, Erik
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Rivera, María Teresa
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Toro, Gonzalo de
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Ortega, Alejandro
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Müller, Bettina
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Gabler, Fernando
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Scherer, Dominique
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Waldenberger, Melanie
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Reischl, Eva
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Boekstegers, Félix
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Garate Calderón, Valentina
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Umu, Sinan U.
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Rounge, Trine B.
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Popanda, Odilia
Author
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Bermejo, Justo Lorenzo
Admission date
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2022-01-17T18:26:42Z
Available date
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2022-01-17T18:26:42Z
Publication date
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2021
Cita de ítem
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Hepatology, Vol . 73, No. 6, 2021
es_ES
Identifier
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10.1002/hep.31585
Identifier
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https://repositorio.uchile.cl/handle/2250/183732
Abstract
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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.
APP ROA CH AND RESULT S: To perform epigenomewide
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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Patrocinador
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Projekt DEAL
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Lenguage
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en
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Publisher
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Wiley
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Type of license
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Attribution-NonCommercial-NoDerivs 3.0 United States