Evolutionary Distance Predicts Recurrence After Liver Transplantation in Multifocal Hepatocellular Carcinoma

Transplantation. 2018 Oct;102(10):e424-e430. doi: 10.1097/TP.0000000000002356.


Background: Liver transplantation (LTx) is a potentially curative treatment option for hepatocellular carcinoma (HCC) in cirrhosis. However, patients, where HCC is already a systemic disease, LTx may be individually harmful and has a negative impact on donor organ usage. Thus, there is a need for improved selection criteria beyond nodule morphology to select patients with a favorable outcome for LTx in multifocal HCC. Evolutionary distance measured from genome-wide single-nucleotide polymorphism data between tumor nodules and the cirrhotic liver may be a prognostic marker of survival after LTx for multifocal HCC.

Methods: In a retrospective multicenter study, clinical data and formalin-fixed paraffin-embedded specimens of the liver and 2 tumor nodules were obtained from explants of 30 patients in the discovery and 180 patients in the replication cohort. DNA was extracted from formalin-fixed paraffin-embedded specimens followed by genome wide single-nucleotide polymorphism genotyping.

Results: Genotype quality criteria allowed for analysis of 8 patients in the discovery and 17 patients in the replication set. DNA concentrations of a total of 25 patients fulfilled the quality criteria and were included in the analysis. Both, in the discovery (P = 0.04) and in the replication data sets (P = 0.01), evolutionary distance was associated with the risk of recurrence of HCC after transplantation (combined P = 0.0002). In a univariate analysis, evolutionary distance (P = 7.4 × 10) and microvascular invasion (P = 1.31 × 10) were significantly associated with survival in a Cox regression analysis.

Conclusions: Evolutionary distance allows for the determination of a high-risk group of recurrence if preoperative liver biopsy is considered.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / analysis
  • Biopsy
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / surgery
  • Evolution, Molecular
  • Female
  • Follow-Up Studies
  • Genotyping Techniques
  • Humans
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / surgery
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / surgery
  • Liver Transplantation*
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / diagnosis*
  • Neoplasm Recurrence, Local / genetics
  • Patient Selection
  • Phylogeny
  • Polymorphism, Single Nucleotide / genetics
  • Preoperative Period
  • Prognosis
  • Regression Analysis
  • Retrospective Studies
  • Treatment Outcome
  • Whole Genome Sequencing


  • Biomarkers