Gabriela Hernandez-Meza1, Johann von Felden1,2, Edgar E Gonzalez-Kozlova3, Teresa Garcia-Lezana1, Judit Peix4, Anna Portela5, Amanda J Craig1, Sergi Sayols5,6, Myron Schwartz7, Bojan Losic3,8,9, Vincenzo Mazzaferro10, Manel Esteller11,12,13,14, Josep M Llovet1,4,15, Augusto Villanueva1,16. 1. Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. 2. I. Department of Internal Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany. 3. Department of Genetics and Genomic Sciences, Cancer Immunology Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY. 4. Translational Research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer-Hospital Clínic, Universitat de Barcelona, Catalonia, Spain. 5. Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Spain. 6. Institute of Molecular Biology, Mainz, Germany. 7. Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY. 8. Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY. 9. Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY. 10. Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy. 11. Josep Carreras Leukemia Research Institute, Barcelona, Spain. 12. Centro de Investigacion Biomedica en Red Cancer, Madrid, Spain. 13. Institucio Catalana de Recerca i Estudis Avançats, Barcelona, Spain. 14. Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain. 15. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain. 16. Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Abstract
BACKGROUND AND AIMS: Mutations in TERT (telomerase reverse transcriptase) promoter are established gatekeepers in early hepatocarcinogenesis, but little is known about other molecular alterations driving this process. Epigenetic deregulation is a critical event in early malignancies. Thus, we aimed to (1) analyze DNA methylation changes during the transition from preneoplastic lesions to early HCC (eHCC) and identify candidate epigenetic gatekeepers, and to (2) assess the prognostic potential of methylation changes in cirrhotic tissue. APPROACH AND RESULTS: Methylome profiling was performed using Illumina HumanMethylation450 (485,000 cytosine-phosphateguanine, 96% of known cytosine-phosphateguanine islands), with data available for a total of 390 samples: 16 healthy liver, 139 cirrhotic tissue, 8 dysplastic nodules, and 227 HCC samples, including 40 eHCC below 2cm. A phylo-epigenetic tree derived from the Euclidean distances between differentially DNA-methylated sites (n = 421,997) revealed a gradient of methylation changes spanning healthy liver, cirrhotic tissue, dysplastic nodules, and HCC with closest proximity of dysplasia to HCC. Focusing on promoter regions, we identified epigenetic gatekeeper candidates with an increasing proportion of hypermethylated samples (beta value > 0.5) from cirrhotic tissue (<1%), to dysplastic nodules (≥25%), to eHCC (≥50%), and confirmed inverse correlation between DNA methylation and gene expression for TSPYL5 (testis-specific Y-encoded-like protein 5), KCNA3 (potassium voltage-gated channel, shaker-related subfamily, member 3), LDHB (lactate dehydrogenase B), and SPINT2 (serine peptidase inhibitor, Kunitz type 2) (all P < 0.001). Unsupervised clustering of genome-wide methylation profiles of cirrhotic tissue identified two clusters, M1 and M2, with 42% and 58% of patients, respectively, which correlates with survival (P < 0.05), independent of etiology. CONCLUSIONS: Genome-wide DNA-methylation profiles accurately discriminate the different histological stages of human hepatocarcinogenesis. We report on epigenetic gatekeepers in the transition between dysplastic nodules and eHCC. DNA-methylation changes in cirrhotic tissue correlate with clinical outcomes.
BACKGROUND AND AIMS: Mutations in TERT (telomerase reverse transcriptase) promoter are established gatekeepers in early hepatocarcinogenesis, but little is known about other molecular alterations driving this process. Epigenetic deregulation is a critical event in early malignancies. Thus, we aimed to (1) analyze DNA methylation changes during the transition from preneoplastic lesions to early HCC (eHCC) and identify candidate epigenetic gatekeepers, and to (2) assess the prognostic potential of methylation changes in cirrhotic tissue. APPROACH AND RESULTS: Methylome profiling was performed using Illumina HumanMethylation450 (485,000 cytosine-phosphateguanine, 96% of known cytosine-phosphateguanine islands), with data available for a total of 390 samples: 16 healthy liver, 139 cirrhotic tissue, 8 dysplastic nodules, and 227 HCC samples, including 40 eHCC below 2cm. A phylo-epigenetic tree derived from the Euclidean distances between differentially DNA-methylated sites (n = 421,997) revealed a gradient of methylation changes spanning healthy liver, cirrhotic tissue, dysplastic nodules, and HCC with closest proximity of dysplasia to HCC. Focusing on promoter regions, we identified epigenetic gatekeeper candidates with an increasing proportion of hypermethylated samples (beta value > 0.5) from cirrhotic tissue (<1%), to dysplastic nodules (≥25%), to eHCC (≥50%), and confirmed inverse correlation between DNA methylation and gene expression for TSPYL5 (testis-specific Y-encoded-like protein 5), KCNA3 (potassium voltage-gated channel, shaker-related subfamily, member 3), LDHB (lactate dehydrogenase B), and SPINT2 (serine peptidase inhibitor, Kunitz type 2) (all P < 0.001). Unsupervised clustering of genome-wide methylation profiles of cirrhotic tissue identified two clusters, M1 and M2, with 42% and 58% of patients, respectively, which correlates with survival (P < 0.05), independent of etiology. CONCLUSIONS: Genome-wide DNA-methylation profiles accurately discriminate the different histological stages of human hepatocarcinogenesis. We report on epigenetic gatekeepers in the transition between dysplastic nodules and eHCC. DNA-methylation changes in cirrhotic tissue correlate with clinical outcomes.
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