Oncotarget

Research Papers:

Nonlinear tumor evolution from dysplastic nodules to hepatocellular carcinoma

Je-Gun Joung, Sang Yun Ha, Joon Seol Bae, Jae-Yong Nam, Geum-Youn Gwak, Hae-Ock Lee, Dae-Soon Son, Cheol-Keun Park _ and Woong-Yang Park

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Oncotarget. 2017; 8:2076-2082. https://doi.org/10.18632/oncotarget.10502

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Abstract

Je-Gun Joung1,*, Sang Yun Ha5,*, Joon Seol Bae1, Jae-Yong Nam1,2, Geum-Youn Gwak6, Hae-Ock Lee1,4, Dae-Soon Son1,3, Cheol-Keun Park5, Woong-Yang Park1,2,4

1Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

2Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

3Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

4Departments of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

5Departments of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

6Departments of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

*These authors have contributed equally to this work

Correspondence to:

Cheol-Keun Park, email: [email protected]

Woong-Yang Park, email: [email protected]

Keywords: hepatocellular carcinoma, dysplastic nodules, whole-exome sequencing, single nucleotide variation, copy number variation

Received: October 24, 2015    Accepted: May 17, 2016    Published: July 09, 2016

ABSTRACT

Dysplastic nodules are premalignant neoplastic nodules found in explanted livers with cirrhosis. Genetic signatures of premalignant dysplastic nodules (DNs) with concurrent hepatocellular carcinoma (HCC) may provide an insight in the molecular evolution of hepatocellular carcinogenesis. We analyzed four patients with multifocal nodular lesions and cirrhotic background by whole-exome sequencing (WES). The genomic profiles of somatic single nucleotide variations (SNV) and copy number variations (CNV) in DNs were compared to those of HCCs. The number and variant allele frequency of somatic SNVs of DNs and HCCs in each patient was identical along the progression of pathological grade. The somatic SNVs in DNs showed little conservation in HCC. Additionally, CNVs showed no conservation. Phylogenetic analysis based on SNVs and copy number profiles indicated a nonlinear segregation pattern, implying independent development of DNs and HCC in each patient. Thus, somatic mutations in DNs may be developed separately from other malignant nodules in the same liver, suggesting a nonlinear model for hepatocarcinogenesis from DNs to HCC.


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