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

PLoS Med. 2014 Dec 23;11(12):e1001770. doi: 10.1371/journal.pmed.1001770. eCollection 2014 Dec.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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

Substances

  • STAT3 Transcription Factor

Associated data

  • GEO/GSE12720
  • GEO/GSE14520
  • GEO/GSE15239
  • GEO/GSE22058
  • GEO/GSE39791

Grants and funding

This work is supported in part by 2011 and 2012 cycle of MD Anderson Sister Institute Network Fund (JSL); Bio & Medical Technology Development Program Grant M10642040002-07N4204-00210 (WJ); Scientific Research Center Program Grant 2012R1A5A1048236 (WJ); the GlaxoSmithKline Research Fund of the Korean Association for the Study of the Liver (JHK); the intramural program of the Center for Cancer Research, National Cancer Institute (XWW and SST); and the National Research Foundation (NSF); of Korea grant by the Korea government (Ministry of Science, ICT, and Future Planning) (No. 2013R1A2A2A05005990) (YNP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.