Cholestasis is a marker for hepatocellular carcinomas displaying beta-catenin mutations

J Pathol. 2007 Jul;212(3):345-52. doi: 10.1002/path.2169.


The Wnt/beta-catenin signalling pathway is activated in many human hepatocellular carcinomas (HCC). Identification of beta-catenin mutation relies mostly on sequence analysis and/or immunohistochemistry. beta-catenin mutation may also be detected by analysing the expression of its target genes. The GLUL gene encoding glutamine synthetase (GS), for example, appears to be a pertinent marker. The aim of this study was to correlate GS immunostaining and beta-catenin mutations with clinicopathological features in HCC. We found that GS immunostaining had a sensitivity of 90% for the detection of beta-catenin mutations, with 98% specificity, whereas beta-catenin immunostaining had a sensitivity of 63% with 98% specificity. We used the sensitive GS marker to characterize 190 HCC cases. Sixty-eight (36%) cases displayed Wnt/beta-catenin activation. In addition to their well-differentiated pattern, these tumours exhibited significant features such as a homogeneous microtrabeculo-acinar pattern, low-grade cellular atypia, and cholestasis. As these tumours exhibited cholestasis, we hypothesized that beta-catenin acts on specific bile synthesis and/or transport pathways. In conclusion, we propose that GS immunostaining and a cholestatic pattern are relevant criteria for the identification of HCC with beta-catenin mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / genetics
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Chi-Square Distribution
  • Cholestasis / genetics
  • Cholestasis / metabolism
  • Cholestasis / pathology*
  • DNA Mutational Analysis
  • Gene Expression
  • Glutamate-Ammonia Ligase / analysis*
  • Glutamate-Ammonia Ligase / genetics
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Mutation
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sensitivity and Specificity
  • Signal Transduction
  • Wnt1 Protein / metabolism
  • beta Catenin / analysis
  • beta Catenin / genetics*
  • beta Catenin / metabolism


  • Biomarkers, Tumor
  • Wnt1 Protein
  • beta Catenin
  • Glutamate-Ammonia Ligase