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Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation.

 Ji Hoon Kim  ;  Bo Hwa Sohn  ;  Hyun Sung Lee  ;  Sang Bae Kim  ;  Jeong Eun Yoo  ;  Yun Yong Park  ;  Woojin Jeong  ;  Sung Sook Lee  ;  Eun Sung Park  ;  Ahmed Kaseb  ;  Baek Hui Kim  ;  Wan Bae Kim  ;  Jong Eun Yeon  ;  Kwan Soo Byun  ;  In Sun Chu  ;  Sung Soo Kim  ;  Xin Wei Wang  ;  Snorri S. Thorgeirsson  ;  John M. Luk  ;  Koo Jeong Kang  ;  Jeonghoon Heo  ;  Young Nyun Park  ;  Ju Seog Lee 
 PLOS MEDICINE, Vol.11(12) : e1001770, 2014 
Journal Title
Issue Date
Adult ; Aged ; Carcinoma, Hepatocellular/genetics* ; Female ; Humans ; Liver Neoplasms/genetics* ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasm Recurrence, Local/genetics ; Risk Factors ; STAT3 Transcription Factor/genetics ; Young Adult
BACKGROUND: Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications.
METHODS AND FINDINGS: Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3-3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1-2.6; p = 0.01). The potential significance of STAT3 activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus-positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus.
CONCLUSIONS: Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification. Please see later in the article for the Editors' Summary.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Park, Eun Sung(박은성)
Yoo, Jeong Eun(유정은) ORCID logo https://orcid.org/0000-0001-9990-279X
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