Journal
HEPATOLOGY
Volume 74, Issue 1, Pages 183-199Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1002/hep.31659
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Funding
- German Research Foundation [FE1746/1-1]
- Clinician Scientist Program at the University Medical Center Hamburg
- Spanish Association for the Study of the Liver
- National Cancer Institute Ruth L. Kirschstein NRSA Institutional Research Training Grant [CA078207]
- Icahn Institute of Genomics and Multiscale Biology
- European Commission Horizon 2020 Program [667273-2]
- US Department of Defense (CA150272P3)
- National Cancer Institute [P30 CA196521]
- Samuel Waxman Cancer Research Foundation
- Spanish National Health Institute [SAF-2016-76390, PID2019-105378RB-I00]
- partnership among Cancer Research UK
- Fondazione AIRC
- Fundacion Cientifica de la Asociacion Espanola Contra el Cancer [C9380/A26813]
- Generalitat de Catalunya [SGR-1358]
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This study identified DNA methylation changes during the transition from preneoplastic lesions to early HCC and potential epigenetic gatekeepers. Additionally, methylation changes in cirrhotic tissue were found to 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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