Johannes Brägelmann1,2,3, Carol Barahona Ponce1,4, Katherine Marcelain4, Stephanie Roessler5, Benjamin Goeppert5, Ivan Gallegos6, Alicia Colombo4,6, Verónica Sanhueza7, Erik Morales8, María Teresa Rivera9, Gonzalo de Toro10, Alejandro Ortega11, Bettina Müller12, Fernando Gabler13, Dominique Scherer1, Melanie Waldenberger14, Eva Reischl14, Felix Boekstegers1, Valentina Garate-Calderon1,4, Sinan U Umu15, Trine B Rounge15,16, Odilia Popanda17, Justo Lorenzo Bermejo1. 1. Statistical Genetics Research Group, Institute of Medical Biometry and Informatic, University of Heidelberg, Heidelberg, Germany. 2. Molecular Pathology, Institute of Pathology & Department of Translational Genomics, University Hospital of Cologne, Cologne, Germany. 3. Mildred Scheel School of Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany. 4. Department of Basic and Clinical Oncology, Medical Faculty, University of Chile, Santiago, Chile. 5. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 6. Servicio de Anatomía Patológica, Hospital Clínico de la Universidad de Chile, Santiago, Chile. 7. Servicio de Anatomía Patológica, Hospital Padre Hurtado, Santiago, Chile. 8. Facultad de Medicina, Universidad Catolica del Maule & Unidad de Anatomia Patologica del Hospital Regional de Talca, Talca, Chile. 9. Servicio de Anatomía Patológica, Hospital del Salvador, Santiago, Chile. 10. Escuela de Tecnologia Medica, Universidad Austral de Chile sede Puerto Montt & Servicio de Anatomía Patológica, Hospital de Puerto Montt, Puerto Montt, Chile. 11. Servicio de Anatomía Patológica, Hospital Regional, Arica, Chile. 12. Servicio de Oncología Médica, Instituto Nacional del Cáncer, Santiago, Chile. 13. Unidad de Anatomia Patologica, Hospital San Borja Arriaran, Santiago, Chile. 14. Research Unit of Molecular Epidemiology and Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. 15. Department of Research, Cancer Registry of Norway, Oslo, Norway. 16. Department of Informatics, University of Oslo, Oslo, Norway. 17. Division of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany.
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.
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.
Authors: Daniel Desaulniers; Paule Vasseur; Abigail Jacobs; M Cecilia Aguila; Norman Ertych; Miriam N Jacobs Journal: Int J Mol Sci Date: 2021-10-11 Impact factor: 5.923
Authors: Alice Blandino; Dominique Scherer; Trine B Rounge; Sinan U Umu; Felix Boekstegers; Carol Barahona Ponce; Katherine Marcelain; Valentina Gárate-Calderón; Melanie Waldenberger; Erik Morales; Armando Rojas; César Munoz; Javier Retamales; Gonzalo de Toro; Olga Barajas; María Teresa Rivera; Analía Cortés; Denisse Loader; Javiera Saavedra; Lorena Gutiérrez; Alejandro Ortega; Maria Enriqueta Bertrán; Fernando Gabler; Mónica Campos; Juan Alvarado; Fabrizio Moisán; Loreto Spencer; Bruno Nervi; Daniel E Carvajal-Hausdorf; Héctor Losada; Mauricio Almau; Plinio Fernández; Ivan Gallegos; Jordi Olloquequi; Macarena Fuentes-Guajardo; Rolando Gonzalez-Jose; Maria Cátira Bortolini; Carla Gallo; Andres Ruiz Linares; Francisco Rothhammer; Justo Lorenzo Bermejo Journal: Cancers (Basel) Date: 2022-01-27 Impact factor: 6.639