DNA Methylation Profiling of Human Hepatocarcinogenesis

被引：70

作者：

Hernandez-Meza, Gabriela ^{[1
]}

von Felden, Johann ^{[1
,2
]}

Gonzalez-Kozlova, Edgar E. ^{[3
]}

Garcia-Lezana, Teresa ^{[1
]}

Peix, Judit ^{[4
]}

Portela, Anna ^{[5
]}

Craig, Amanda J. ^{[1
]}

Sayols, Sergi ^{[5
,6
]}

Schwartz, Myron ^{[7
]}

Losic, Bojan ^{[3
,8
,9
]}

Mazzaferro, Vincenzo ^{[10
]}

Esteller, Manel ^{[11
,12
,13
,14
]}

Llovet, Josep M. ^{[1
,4
,15
]}

Villanueva, Augusto ^{[1
,16
]}

机构：

[1] 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

[2] Univ Med Ctr Hamburg Eppendorf, Dept Internal Med, Hamburg, Germany

[3] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Canc Immunol Program, Dept Genet & Genom Sci, New York, NY 10029 USA

[4] Univ Barcelona, Translat Res Hepat Oncol, Inst Invest Biomed August Pi & Sunyer, Liver Unit,Hosp Clin, Catalonia, Spain

[5] Bellvitge Biomed Res Inst, Canc Epigenet & Biol Program, Barcelona, Spain

[6] Inst Mol Biol, Mainz, Germany

[7] Icahn Sch Med Mt Sinai, Dept Surg, New York, NY 10029 USA

[8] Icahn Sch Med Mt Sinai, Icahn Inst Data Sci & Genom Technol, New York, NY 10029 USA

[9] Icahn Sch Med Mt Sinai, Diabet Obes & Metab Inst, New York, NY 10029 USA

[10] Natl Canc Inst, Gastrointestinal Surg & Liver Transplantat Unit, Milan, Italy

[11] Josep Carreras Leukemia Res Inst, Barcelona, Spain

[12] Ctr Invest Biomed Red Canc, Madrid, Spain

[13] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain

[14] Univ Barcelona, Physiol Sci Dept, Sch Med & Hlth Sci, Barcelona, Spain

[15] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain

[16] Icahn Sch Med Mt Sinai, Dept Med, Div Hematol & Med Oncol, New York, NY 10029 USA

来源：

HEPATOLOGY | 2021年 / 74卷 / 01期

基金：

欧盟地平线“2020”;

关键词：

TUMOR-SUPPRESSOR GENES; HEPATOCELLULAR-CARCINOMA; COLORECTAL-CANCER; EXPRESSION; EPIGENETICS; PROGRESSION; PROGNOSIS; HEPATITIS; TISSUES; EVENTS;

D O I：

10.1002/hep.31659

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：183 / 199

页数：17