DNA Methylation Profiling of Human Hepatocarcinogenesis
Por:
Hernandez-Meza, G, von Felden, J, Gonzalez-Kozlova, EE, Garcia-Lezana, T, Peix, J, Portela, A, Craig, AJ, Sayols, S, Schwartz, M, Losic, B, Mazzaferro, V, Esteller, M, Llovet, JM and Villanueva, A
Publicada:
1 jul 2021
Ahead of Print:
1 jun 2021
Resumen:
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.
Filiaciones:
Hernandez-Meza, G:
Icahn Sch Med Mt Sinai, Dept Med, Tisch Canc Inst, Div Liver Dis,Liver Canc Program, 1425 Madison Ave,Room 1-70E,Box 1123, New York, NY 10029 USA
von Felden, J:
Icahn Sch Med Mt Sinai, Dept Med, Tisch Canc Inst, Div Liver Dis,Liver Canc Program, 1425 Madison Ave,Room 1-70E,Box 1123, New York, NY 10029 USA
Univ Med Ctr Hamburg Eppendorf, Dept Internal Med, Hamburg, Germany
Gonzalez-Kozlova, EE:
Icahn Sch Med Mt Sinai, Tisch Canc Inst, Canc Immunol Program, Dept Genet & Genom Sci, New York, NY 10029 USA
Garcia-Lezana, T:
Icahn Sch Med Mt Sinai, Dept Med, Tisch Canc Inst, Div Liver Dis,Liver Canc Program, 1425 Madison Ave,Room 1-70E,Box 1123, New York, NY 10029 USA
Peix, J:
Univ Barcelona, Translat Res Hepat Oncol, Inst Invest Biomed August Pi & Sunyer, Liver Unit,Hosp Clin, Catalonia, Spain
Portela, A:
Bellvitge Biomed Res Inst, Canc Epigenet & Biol Program, Barcelona, Spain
Craig, AJ:
Icahn Sch Med Mt Sinai, Dept Med, Tisch Canc Inst, Div Liver Dis,Liver Canc Program, 1425 Madison Ave,Room 1-70E,Box 1123, New York, NY 10029 USA
Sayols, S:
Bellvitge Biomed Res Inst, Canc Epigenet & Biol Program, Barcelona, Spain
Inst Mol Biol, Mainz, Germany
Schwartz, M:
Icahn Sch Med Mt Sinai, Dept Surg, New York, NY 10029 USA
Losic, B:
Icahn Sch Med Mt Sinai, Tisch Canc Inst, Canc Immunol Program, Dept Genet & Genom Sci, New York, NY 10029 USA
Icahn Sch Med Mt Sinai, Icahn Inst Data Sci & Genom Technol, New York, NY 10029 USA
Icahn Sch Med Mt Sinai, Diabet Obes & Metab Inst, New York, NY 10029 USA
Mazzaferro, V:
Natl Canc Inst, Gastrointestinal Surg & Liver Transplantat Unit, Milan, Italy
:
Josep Carreras Leukemia Res Inst, Barcelona, Spain
Ctr Invest Biomed Red Canc, Madrid, Spain
Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain
Univ Barcelona, Physiol Sci Dept, Sch Med & Hlth Sci, Barcelona, Spain
Llovet, JM:
Icahn Sch Med Mt Sinai, Dept Med, Tisch Canc Inst, Div Liver Dis,Liver Canc Program, 1425 Madison Ave,Room 1-70E,Box 1123, New York, NY 10029 USA
Univ Barcelona, Translat Res Hepat Oncol, Inst Invest Biomed August Pi & Sunyer, Liver Unit,Hosp Clin, Catalonia, Spain
Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain
Villanueva, A:
Icahn Sch Med Mt Sinai, Dept Med, Tisch Canc Inst, Div Liver Dis,Liver Canc Program, 1425 Madison Ave,Room 1-70E,Box 1123, New York, NY 10029 USA
Icahn Sch Med Mt Sinai, Dept Med, Div Hematol & Med Oncol, New York, NY 10029 USA
Green Accepted, Green Submitted, Bronze
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