title: Cholestasis is a marker for hepatocellular carcinomas displaying beta-catenin mutations.
abstract: 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.
authors.affiliation: Institut Cochin, Département EMC, Paris, F-75014, France.
authors.forename: V
authors.initials: V
authors.lastname: Audard
authors.forename: G
authors.initials: G
authors.lastname: Grimber
authors.forename: C
authors.initials: C
authors.lastname: Elie
authors.forename: B
authors.initials: B
authors.lastname: Radenen
authors.forename: A
authors.initials: A
authors.lastname: Audebourg
authors.forename: F
authors.initials: F
authors.lastname: Letourneur
authors.forename: O
authors.initials: O
authors.lastname: Soubrane
authors.forename: M-C
authors.initials: MC
authors.lastname: Vacher-Lavenu
authors.forename: C
authors.initials: C
authors.lastname: Perret
authors.forename: C
authors.initials: C
authors.lastname: Cavard
authors.forename: B
authors.initials: B
authors.lastname: Terris
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016009:Chi-Square Distribution; D002779:Cholestasis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004252:DNA Mutational Analysis; D015870:Gene Expression; D005974:Glutamate-Ammonia Ligase / Q000032:analysis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D051155:Wnt1 Protein / Q000378:metabolism; D051176:beta Catenin / Q000032:analysis / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D051155:Wnt1 Protein; D051176:beta Catenin; D005974:Glutamate-Ammonia Ligase