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Dynamics of Genomic, Epigenomic, and Transcriptomic Aberrations during Stepwise Hepatocarcinogenesis

 Byul A Jee  ;  Ji-Hye Choi  ;  Hyungjin Rhee  ;  Sarah Yoon  ;  So Mee Kwon  ;  Ji Hae Nahm  ;  Jeong Eun Yoo  ;  Youngsic Jeon  ;  Gi Hong Choi  ;  Hyun Goo Woo  ;  Young Nyun Park 
 CANCER RESEARCH, Vol.79(21) : 5500-5512, 2019 
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Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., DKK3, SALL3, and SOX1) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress-related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis. SIGNIFICANCE: Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.
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1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Nahm, Ji Hae(남지해) ORCID logo https://orcid.org/0000-0003-0902-866X
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Yoo, Jeong Eun(유정은) ORCID logo https://orcid.org/0000-0001-9990-279X
Rhee, Hyungjin(이형진) ORCID logo https://orcid.org/0000-0001-7759-4458
Choi, Gi Hong(최기홍) ORCID logo https://orcid.org/0000-0002-1593-3773
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